Thalidomide Does Not Improve Survival In Small Cell Lung Cancer, Study Finds

Treating patients with thalidomide in combination with chemotherapy for small cell lung cancer (SCLC) did not improve their survival but did increase their risk of blood clots, according to a new study published online July 16 in the Journal of the National Cancer Institute.

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Siow Ming Lee, M.D., of the Department of Oncology, University Hospital in London, and colleagues randomly assigned 724 SCLC patients to take either a placebo or thalidomide. Used in treating some other cancers, thalidomide is an anti-angiogenic drug, i.e., it targets and suppresses the formation of new blood vessels that tumors need to survive and grow. In this randomized double-blind trial, patients received 100-200 milligrams daily for up to two years.

The researchers found no evidence of a survival difference between the two groups. The median overall survival for patients who received the placebo was 10.5 months. For patients who took thalidomide capsules, it was 10.1 months. Patients treated with thalidomide, however, had higher risk of thrombotic events.

"Together, these results suggest that targeting anti-angiogenesis in SCLC may not work as well as in multiple myeloma or colorectal cancer, perhaps because of differences in the angiogenic pathways involved in SCLC," the authors write.

In an accompanying editorial, Curzio Rüegg, M.D., of the Division of Experimental Oncology at the University of Lausanne in Switzerland, and Solange Peters, M.D., Ph.D., of the Clinical Oncology Service at the University of Lausanne, note that this study's results, as well as similar, negative results from previous studies, should lead to a fresh look at the basic biology of SCLC and of the putative anti-angiogenic activity of thalidomide.

"Rather than running from failure to failure, it may be more reasonable to go back to experimental work, including the development and analysis of transgenic SCLC models, to better understand SCLC biology and identify robust therapeutic targets," the editorialists write.

Source : http://www.sciencedaily.com/releases/2009/07/090716164337.htm

Sleep-Disordered Breathing Linked With Behavior Problems in Asthma

Sleep-disordered breathing (SDB) is associated with behavior problems in children with asthma, according to a paper in the July issue of Pediatrics.

Dr. Maria Fagnano and colleagues from the University of Rochester School of Medicine, New York, write, "Studies have linked asthma symptoms with both childhood behavior problems and troubled sleep. There is growing, but limited, evidence that children with SDB may have worse behavior."

The investigators' study involved 194 inner-city children with asthma who were between the ages of 4 and 10 years (mean age, 8.2). On the basis of scores on the Sleep-Related Breathing Disorder scale, 33% of the children had SDB, the investigators report. Also, they found, on the basis of caregiver responses on the Behavioral Problem Index (BPI), 32% of children had significant behavioral issues.

Children with SDB had significantly worse behavior scores overall compared to those with no sleep difficulties (p<0.001), p="0.013)," p="0.011)," p="0.014).

On multiple regression analyses, SBD remained significantly associated with total BPI scores and eternalizing, internalizing, anxious/depressed, headstrong, and hyperactive behaviors. Similar significant associations were observed between higher sleep scores and worse behaviors across sleep subscales (snoring and sleepiness).

"Additional investigation is needed to determine if treatment of sleep disorders would help to decrease behavior problems in this population," the authors said.

In the meantime, the researchers conclude, "Clinicians should be particularly diligent about screening all children with asthma for SDB, and consider sleep disorders as a possible risk factor for behavior problems."

Pediatrics 2009;124:218-225.

Source : http://www.medscape.com/viewarticle/705784?sssdmh=dm1.499423&src=nldne

Prasugrel Approved for Use During PCI, FDA Announces

The US FDA has granted the market go-ahead to prasugrel (Effient, Lilly/Daiichi Sankyo), an antiplatelet agent in the same chemical class as clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis), during PCI in the setting of ACS, the agency has announced in a press release [1]. The FDA review of prasugrel's application took about 18 months.

The approval is based primarily on the strength of the TRITON-TIMI 38 trial, which compared prasugrel against clopidogrel in 13 608 patients with moderate- to high-risk unstable angina, ST-segment-elevation MI (STEMI), or non-ST-segment-elevation MI (NSTEMI). Prasugrel was given as a 60-mg loading dose followed by 10-mg/day maintenance, and clopidogrel was given as a 300-mg loading dose plus 75-mg/day maintenance for six to 15 months.

In their announcement of the approval [2], Daiichi Sankyo and Lilly say the drug should be given at the dosage used in the trial. "In addition, for those patients who weigh less than 132 pounds (60 kg), physicians should consider lowering the maintenance dose to 5 mg once daily. Patients taking Effient should also take 75 mg to 325 mg aspirin orally once daily, according to their doctors' instructions."

As reported by heartwire when the TRITON-TIMI 38 was presented at the AHA 2007 Scientific Sessions, patients who received prasugrel showed a significant 19% reduction in the primary composite end point of cardiovascular death, MI, and stroke in the entire ACS population. The benefit was about the same across the three kinds of ACS.

The FDA's Cardiovascular and Renal Drugs Advisory Committee unanimously recommended the drug's approval in February 2009, as reported at the time by heartwire . During the hearing, most panel members said they felt comfortable supporting a superiority claim for prasugrel over clopidogrel in ACS patients, despite an increased risk of clinically significant bleeding observed with the newer drug in TRITON-TIMI 38.

According to the FDA announcement, prasugrel's labeling will include "a boxed warning alerting physicians that the drug can cause significant, sometimes fatal, bleeding. The drug should not be used in patients with active pathological bleeding, a history of ministrokes (transient ischemic attacks) or stroke, or urgent need for surgery, including coronary artery bypass graft surgery."

"Effient offers physicians an alternative treatment for preventing dangerous blood clots from forming and causing a heart attack or stroke during or after an angioplasty procedure," said Dr John Jenkins, director of the Office of New Drugs, in the FDA’s Center for Drug Evaluation and Research, in the agency's announcement. "Physicians must carefully weigh the potential benefits and risks of Effient as they decide which patients should receive the drug."

Source : http://www.medscape.com/viewarticle/705725?sssdmh=dm1.499002&src=nldne

Why H1N1 Flu Spreads Inefficiently

A team from MIT and the Centers for Disease Control and Prevention has found a genetic explanation for why the new H1N1 "swine flu" virus has spread from person to person less effectively than other flu viruses.

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The H1N1 strain, which circled the globe this spring, has a form of surface protein that binds inefficiently to receptors found in the human respiratory tract, the team reports in the July 2 online edition of Science.

"While the virus is able to bind human receptors, it clearly appears to be restricted," says Ram Sasisekharan, the Edward Hood Taplin Professor and director of the Harvard-MIT Division of Health Sciences and Technology (HST) and the lead MIT author of the paper. Sasisekharan and his laboratory co-workers have been actively investigating influenza viruses.

That restricted, or weak, binding, along with a genetic variation in an H1N1 polymerase enzyme, which MIT researchers first reported three weeks ago in Nature Biotechnology, explains why the virus has not spread as efficiently as seasonal flu, says Sasisekharan. However, flu viruses are known to mutate rapidly, so there is cause for concern if H1N1 undergoes mutations that improve its binding affinity.

"We need to pay careful attention to the evolution of this virus," says Sasisekharan.

On June 11, the World Health Organization declared a level 6 pandemic alert for H1N1. More than 300 people have died and more than 70,000 people have been infected, according to the WHO.

Genetic variation

Sasisekharan and CDC senior microbiologist Terrence Tumpey have previously shown that a flu virus's ability to infect humans depends on whether its hemagglutinin protein can bind to a specific type of receptor on the surface of human respiratory cells.

In the new Science paper, Sasisekharan, Tumpey and colleagues compared the new H1N1 strain to several seasonal flu strains, including some milder H1N1 strains, and to the virus that caused the 1918 flu pandemic. They found that the new strain, as expected, is able to bind to the predominant receptors in the human respiratory tract, known as umbrella-shaped alpha 2-6 glycan receptors.

However, binding efficiency varies between flu strains, and that variation is partly determined by the receptor-binding site (RBS) within the hemagglutinin protein. The team found that the new H1N1 strain's RBS binds human receptors much less effectively than other flu viruses that infect humans.

The researchers also found that the new H1N1 strain spreads inefficiently in ferrets, which accurately mimics human influenza disease including how it spreads or transmits in humans. When the ferrets were in close contact with each other, they were exposed to enough virus particles that infection spread easily. However, when ferrets were kept separate and the virus could spread only through airborne respiratory droplets, the illness spread much less effectively.

This is consistent with the transmission of this virus seen in humans so far, says Sasisekharan. Most outbreaks have occurred in limited clusters, sometimes within a family or a school but not spread much further.

"One of the big payoffs of long-term investments in carbohydrate biology and chemistry research is an understanding of the relationships between cell surface carbohydrate structure and viral infectivity," said Jeremy M. Berg, director of the National Institute of General Medical Sciences of the National Institutes of Health, which partly funded the research. "Tools developed in building such understanding help in the response to events like the recent H1N1 outbreak."

Second mutation

The researchers also pinpointed a second mutation that impairs H1N1's ability to spread rapidly.

Recent studies have shown that a viral RNA polymerase known as PB2 is critical for efficient influenza transmissibility. (RNA polymerase controls the viruses' replication once they infect a host.) The new H1N1 strain does not have the version of the PB2 gene necessary for efficient transmission.

MIT researchers led by Sasisekharan first reported the PB2 work in the June 9 online issue of Nature Biotechnology. That study also found that the new H1N1 strain has substantial genetic variability in the proteins targeted by current vaccines, making it likely that existing seasonal vaccines will be ineffective against the new strain.

Moreover, the researchers discovered that the new strain might just need a single change or mutation that could lead to inefficient interaction with the influenza drug oseltamivir, commonly known as Tamiflu, raising the possibility that strains resistant to Tamiflu could emerge easily.

The research done at MIT was funded by the Singapore-MIT Alliance for Research and Technology and the National Institutes of General Medical Sciences.

Source : http://www.sciencedaily.com/releases/2009/07/090702140849.htm

Chronic Kidney Disease and its Management

Chronic kidney disease represents the gradual, substantial, and irreversible reduction in the excretory and homeostatic functions of the kidneys. It is characterised by progressive destruction of renal tissue over a period of at least months to many years, depending on the underlying aetiology. Glomerular filtration rate (GFR) progressively decreases with loss of functioning nephrons.

Until recently, the emphasis has been on patients needing dialysis or transplantation. It is now realised that less severe CKD is quite common, and monitoring in primary care will enable the minority of patients who go on to develop a more severe form to be detected at any earlier stage.¹ This important because the earlier the intervention, the greater the impact. Patients with chronic conditions such as heart disease and diabetes may already undergo structured review in primary care but the full extent of reduced kidney function may not be recognised.²

Classification of chronic kidney disease³

Kidney function should be assessed by estimated GFR (eGFR) and chronic kidney disease (CKD) is classified on this basis. The GFR should be estimated from serum creatinine using the 4-variable Modification of Diet in Renal Disease (MDRD) equation (see under investigations below).⁴

Patients with a GFR of >60 ml/min/1.73 m2 without evidence of chronic kidney damage should NOT be considered to have CKD and do not necessarily need further investigation.

• Stage 1: normal; eGFR >90 ml/min/1.73 m² with other evidence of chronic kidney damage (see below)
• Stage 2: mild impairment; eGFR 60-89 ml/min/1.73 m² with other evidence of chronic kidney damage
• Stage 3a: moderate impairment; eGFR 45-59 ml/min/1.73 m²
• Stage 3b: moderate impairment; eGFR 30-44 ml/min/1.73 m²
• Stage 4: severe impairment; eGFR 15-29 ml/min/1.73 m²
• Stage 5: established renal failure (ERF); eGFR less than 15 ml/min/1.73 m² or on dialysis

Use the suffix (p) to denote the presence of proteinuria when staging CKD.

The other evidence of chronic kidney damage may be one of the following:

• Persistent microalbuminuria
• Persistent proteinuria
• Persistent haematuria (after exclusion of other causes, e.g. urological disease)
• Structural abnormalities of the kidneys demonstrated on ultrasound scanning or other radiological tests, e.g. polycystic kidney disease, reflux nephropathy
• Biopsy-proven chronic glomerulonephritis

Epidemiology

• The incidence of chronic kidney disease requiring dialysis varies worldwide: the number of patients per million population starting dialysis each year is 110 in the UK.³
• The prevalence of end-stage renal failure also varies worldwide: the number of patients per million population in the UK is 498.³

Causes

The most important causes of chronic kidney disease are diabetes, glomerulonephritis, hypertension and other vascular disease.

• Arteriopathic renal disease and hypertension
• Glomerulonephritis
• Diabetes
• Infective, obstructive and reflux nephropathies
• Familial or hereditary kidney disease, e.g. polycystic kidneys
• Hypercalcaemia
• Connective tissue diseases
• Neoplasms
• Myeloma

Risk factors

Factors other than the underlying disease process that may cause progressive renal injury include the following:

• Hypertension
• Acute insults from nephrotoxins or decreased perfusion
• Proteinuria
• Increased renal ammonia formation with interstitial injury
• Hyperlipidaemia
• Hyperphosphataemia with calcium phosphate deposition

Presentation

Symptoms

• Usually presents with non-specific symptoms caused by renal failure, complications (e.g. anaemia in chronic renal failure) and the underlying disease.
• May be discovered by chance following a routine blood or urine test.
• Specific symptoms usually develop only in severe renal failure, and include anorexia, nausea, vomiting, fatigue, weakness, pruritus, lethargy, peripheral oedema, dyspnoea, insomnia, muscle cramps, pulmonary oedema, nocturia, polyuria and headache.
• Sexual dysfunction is common.
• Hiccups, pericarditis, coma and seizures are only seen in very severe renal failure.

Signs

• The physical examination is often not very helpful but may reveal findings characteristic of the underlying cause (e.g. SLE, severe arteriosclerosis, hypertension) or complications of CRF (e.g. anaemia, bleeding diathesis, pericarditis).
• Signs of CKD include increased skin pigmentation or excoriation, pallor, hypertension, postural hypotension, peripheral oedema, left ventricular hypertrophy, peripheral vascular disease, pleural effusions, peripheral neuropathy and restless legs syndrome.

Differential diagnosis

• Acute renal failure:
  • Making the distinction between acute renal failure and chronic renal failure can be very difficult. A history of chronic symptoms of fatigue, weight loss, anorexia, nocturia, and pruritus all suggest chronic kidney disease.
  • The history and examination will provide clues, but renal ultrasound will provide the most important information. Renal abnormalities on ultrasound, such as small kidneys in chronic glomerulonephritis or large cystic kidneys in adult polycystic kidney disease, will almost always be present in patients with chronic kidney disease.
• Acute on chronic renal failure: may have features indicating chronic kidney disease but also features suggesting a cause of an acute deterioration of renal function, e.g. infection.

Investigations

Investigations are focused on assessment of renal function and therefore stage of CKD, identification of the underlying cause and assessment of complications of CKD.

• Assessment of renal function:
  • Serum urea is a poor marker of renal function, because it varies significantly with hydration and diet, is not produced constantly and is reabsorbed by the kidney.
  • Serum creatinine also has significant limitations. The level can remain within the normal range despite the loss of over 50% of renal function.
  • A gold-standard measurement is an isotopic GFR, but this is expensive and not widely available.
  • For most purposes in primary care, the best assessment or screening tool is the estimated glomerular filtration rate (eGFR).⁵ This uses the 4-variable Modification of Diet in Renal Disease (MDRD) equation³ - see the record Assessing Kidney Function and the Estimated Glomerular Filtration Rate Calculator based on this equation. Most laboratories now provide an estimated GFR (eGFR) when requesting serum creatinine which should be used in preference to calculator above.
• Biochemistry:
  • Plasma glucose: to detect undiagnosed diabetes or assess diabetes control
  • Serum sodium: usually normal, but may be low
  • Serum potassium: raised
  • Serum bicarbonate: low
  • Serum albumin: hypoalbuminaemia in patients who are nephrotic and/or malnourished (low levels at the start of dialysis are associated with a poor prognosis)
  • Serum calcium: may be normal, low or high
  • Serum phosphate: usually high
  • Serum alkaline phosphatase: raised when bone disease develops
  • Serum parathyroid hormone: rises progressively with declining renal function
  • Serum cholesterol and triglycerides: dyslipidaemia is common
• Haematology:
  • Normochromic normocytic anaemia; haemoglobin falls with progressive renal failure.
  • White cells and platelets are usually normal.
• Serology:
  • Autoantibodies, particularly antinuclear antibodies, C-ANCA, P-ANCA, anti-glomerular basement membrane antibodies (very suggestive of underlying Goodpasture's syndrome) and serum complement.
  • Hepatitis serology: ensure not infected and vaccinate against hepatitis B.
  • HIV serology: performed before dialysis or transplantation.
• Urine:
  • Urinalysis: dipstick proteinuria may suggest glomerular or tubulointerstitial disease. Urine sediment with red blood cells and red blood cell casts suggests proliferative glomerulonephritis.
  • Pyuria and/or white cell casts suggest interstitial nephritis (especially if eosinophils are present in the urine) or urinary tract infection.
  • Spot urine collection for total protein:creatinine ratio allows reliable estimation of total 24-hour urinary protein excretion. The degree of proteinuria correlates with the rate of progression of the underlying kidney disease and is the most reliable prognostic factor in chronic renal failure.
  • Twenty-four-hour urine collection for total protein and creatinine clearance.
  • Serum and urine protein electrophoresis: to screen for a monoclonal protein possibly representing multiple myeloma.
• ECG and echocardiography: to detect left ventricular hypertrophy and ischaemia, and to assess cardiac function.
• Imaging of the renal tract:
  • Plain abdominal x-ray: may show radio-opaque stones or nephrocalcinosis.
  • Intravenous pyelogram: not often used because of potential for contrast nephropathy.
  • Renal ultrasound:
    • Small echogenic kidneys are seen in advanced renal failure.
    • Kidneys are usually initially large and then become normal in size in advanced diabetic nephropathy.
    • Structural abnormalities may be seen, e.g. polycystic kidneys.
    • Also used to screen for hydronephrosis caused by urinary tract obstruction, or involvement of the retroperitoneum with fibrosis, tumour or diffuse adenopathy.
  • Retrograde pyelogram: may be indicated if clinical suspicion of obstruction despite a negative ultrasound study finding.
  • Renal radionuclide scan:
    • Useful to screen for renal artery stenosis when performed with captopril administration but is unreliable for GFR of less than 30 ml/minute.
    • Also quantifies differential renal contribution to total glomerular filtration rate.
  • CT scan: to better define renal masses and cysts seen on ultrasound; is the most sensitive test for identifying renal stones.
  • MRI:
    • For patients who require a CT scan but who cannot receive intravenous contrast.
    • Like CT scan and renal venography, it is reliable in the diagnosis of renal vein thrombosis.
    • Magnetic resonance angiography is also useful for diagnosis of renal artery stenosis, although renal arteriography remains the investigation of choice.
  • Micturating cystourethrogram: for diagnosis of vesicoureteric reflux.
• Renal biopsy

Criteria for referral to specialist services³

• Estimated GFR less than 15 ml/min/1.73 m²: immediate referral
• Estimated GFR 15-29 ml/min/1.73 m²: urgent referral (routine referral if known to be stable)
• Estimated GFR 30-59 ml/min/1.73 m²: routine referral if:
  • Progressive fall in GFR/increase in serum creatinine
  • Microscopic haematuria present
  • Urinary protein to creatinine ratio greater than 45 mg/mmol
  • Unexplained anaemia (Hb below 11 g/dl); abnormal potassium, calcium or phosphate
  • Suspected systemic illness, eg SLE
  • Uncontrolled BP (above 150/90 mmHg on 3 antihypertensive medications)
• Estimated GFR 60-89 ml/min/1.73 m²: referral not required unless other problems present
• Renal problems irrespective of GFR
  • Immediate referral for:
    • Malignant hypertension
    • Hyperkalaemia (potassium >7.0 mmol/l)
  • Urgent referral for:
    • Proteinuria with oedema and low serum albumin (nephrotic syndrome)
  • Routine referral for:
    • Dipstick proteinuria present and urine protein:creatinine ratio above 100 mg/mmol
    • Dipstick proteinuria and microscopic haematuria present
    • Macroscopic haematuria but urological tests negative

Management

Issues that should be discussed with the patient⁶

• Many patients equate kidney disease with renal dialysis. It is important to explain that CKD a spectrum of disease. Mild CKD is common and rarely progresses to a more severe form later.
• Explain eGFR and that this will need to be monitored on a regular basis to ensure that the condition is not deteriorating.
• If relevant discuss the link between hypertension and CKD and that maintaining tight blood pressure control can limit the damage to the kidneys.
• Discuss the link between CKD and an increased risk of developing cardiovascular disease.

In newly diagnosed with eGFR less than 60 ml/min/1.73 m²

• Review all previous measurements of serum creatinine to estimate GFR and assess rate of deterioration.
• Review all medication including over the counter drugs; particularly consider recent additions (e.g. diuretics, NSAIDs, or any drug capable of causing interstitial nephritis, such as penicillins, cephalosporins, mesalazine, diuretics).
• Urinalysis: haematuria and proteinuria suggest glomerulonephritis, which may progress rapidly.
• Clinical assessment: e.g. look for sepsis, heart failure, hypovolaemia, palpable bladder.
• Repeat serum creatinine measurement within 5 days to exclude rapid progression.
• Check criteria for referral (above). If referral not indicated, ensure entry into a chronic disease management register and programme.

All stages of CKD³

• Regular measurements of kidney function and other laboratory tests depending on the severity of kidney impairment.
• General health advice: smoking cessation, weight loss, aerobic exercise, limiting alcohol intake, limiting sodium intake.
• Avoidance of nephrotoxins, e.g. IV radiocontrast agents, NSAIDs, aminoglycosides.
• Cardiovascular prophylaxis:
  • For patients with 10 year risk of cardiovascular disease of greater than 20%, consider aspirin treatment (if BP is below 150/90 mmHg) and lipid-lowering drug therapy.
  • Blood pressure monitoring: blood pressure should be measured at least annually.
  • Control of hypertension: hypertension should be tightly controlled. The threshold for initiation of anti-hypertensive medication:
    • If urine protein/creatinine ratio (PCR) is below 100 mg/mmol: threshold 140/90 mmHg, target 130/80 mmHg.
    • If urine PCR is above 100 mg/mmol: threshold 130/80 mmHg, target 125/75 mmHg.
• ACE inhibitor or angiotensin receptor blocker to be started:
  • If urine PCR is above 100 mg/mmol.
  • In diabetic patients with micro-albuminuria.
  • Serum creatinine and potassium should be checked before starting medication, two weeks after starting, and after subsequent increases in dose. If creatinine increases by more than 20% or fall in GFR of more than 15%, repeat creatinine, check potassium and refer for specialist opinion on whether to stop treatment or to investigate for renal artery stenosis.
  • If hyperkalaemia is present (serum K above 6 mmol/l): stop relevant drugs, eg. NSAIDs and potassium-retaining diuretics; check diet and proprietary treatments, e.g. LoSalt. If hyperkalaemia persists the ACE or ARB should be stopped.

Additional management for CKD stage 3 includes³

• Annual measurement of haemoglobin, potassium, calcium and phosphate.
• If Hb below 11 g/dl and other causes excluded, treat with erythropoiesis stimulating agents to maintain Hb 11-12 g/dl depending on the patient's functional needs.
• Request renal ultrasound in patients with lower urinary tract symptoms, refractory hypertension, unexpected progressive fall in GFR.
• Immunise against influenza and pneumococcus.
• Review all prescribed medication regularly to ensure appropriate doses.
• Avoid nephrotoxic drugs including NSAIDs wherever possible.
• Check parathyroid hormone concentration when Stage 3 is first diagnosed: if raised, check serum 25-hydroxyvitamin D and if low, treat with ergocalciferol or cholecalciferol with calcium supplement (not calcium phosphate). Repeat PTH after 3 months and refer if still raised.

Additional management for CKD Stages 4-5 includes³

• Care of all patients with stage 4 or 5 CKD should be discussed formally with a nephrologist even if it is not anticipated that renal replacement therapy will be appropriate. Exceptions may include:
  • Patients with another terminal illness.
  • Patients with stable function in whom all the appropriate investigations and management interventions have been performed and who have an agreed and understood care pathway.
  • Patients in whom further investigation and management is clearly inappropriate.
• 3-monthly tests: serum creatinine (for eGFR), Hb, calcium, phosphate, bicarbonate, parathyroid hormone.
• Dietary assessment.
• Immunisation against hepatitis B.
• Investigation and treatment of phosphate retention and hyperparathyroidism.
• Correction of acidosis.
• Timely provision of dialysis access depending on treatment choice.

Renal replacement therapy

Indications for renal replacement therapy (haemodialysis, peritoneal dialysis, chronic ambulatory peritoneal dialysis or renal transplantation) include:

• Serum creatinine greater than 500 mmol/l.
• Symptoms: pericarditis, encephalopathy, peripheral neuropathy, intractable gastrointestinal symptoms, failure to thrive and malnutrition.
• Severe metabolic acidosis: bicarbonate less than 12 mmol/L.

Complications

• Anaemia: left ventricular hypertrophy, fatigue, impaired cognitive functioning
• Coagulopathy
• Hypertension: left ventricular hypertrophy, heart failure, stroke, cardiovascular disease
• Calcium phosphate loading: cardiovascular and cerebrovascular disease, arthropathy, soft tissue calcification
• Renal osteodystrophy: disorders of calcium, phosphorus and bone, most commonly osteitis fibrosa cystica
• Bone changes of secondary hyperparathyroidism: bone pain and fractures
• Neurological: uraemic encephalopathy, neuropathy including peripheral neuropathy
• Dialysis amyloid: bone pain, arthropathy, carpal tunnel syndrome
• Fluid overload: pulmonary oedema, hypertension
• Malnutrition: increased morbidity and mortality, infections, poor wound healing
• Glucose intolerance due to peripheral insulin resistance

Management of complications

• Water and electrolyte balance:
  • Patients with chronic kidney disease pass normal volumes of urine. Precise restriction of fluid intake is only required for patients with oliguric end-stage renal failure. The usual recommendation is for a daily intake of daily urinary output plus 500 ml (for insensible losses).
  • Patients should avoid binge drinking and be vigilant in replacing extra fluid losses in hot weather and during episodes of diarrhoea or vomiting.
  • Severe acute volume overload may require high dose loop diuretics or dialysis.
  • Dietary restriction to 60 mmol/day each of sodium and potassium is appropriate but compliance is greatly improved with sensible and flexible dietary advice.
  • Loop diuretics (with the addition of a thiazide diuretic if resistant) improve sodium balance and blood pressure.
  • Hyperkalaemia is treated with dialysis if the potassium level rises above 7 mmol/L. Otherwise treatment is directed towards the cause, e.g. excess fruit, chocolate or coffee, gastrointestinal haemorrhage, acidosis or tissue necrosis. Hyperkalaemia with the GFR still above 10 ml/min may be due to hyporeninaemic hypoaldosteronism in patients with diabetes, hypoadrenalism or as a result of treatment with ACE inhibitors.
• Anaemia:
  • Erythropoietin is given with iron. The serum ferritin is monitored throughout treatment and iron is stopped if the ferritin level becomes too high, e.g. above 500 mcg/L.
  • Early erythropoietin therapy may prevent left ventricular hypertrophy.
  • The timing for initiation of treatment remains uncertain. The haemoglobin level is usually maintained at or above 11 g/dl.
• Acidosis:
  • Chronic acidosis aggravates hyperkalaemia, inhibits protein synthesis and accelerates calcium loss from bone.
  • Treated with sodium bicarbonate as long as the patient can tolerate the increased sodium load as additional sodium may cause fluid overload and worsen hypertension.
• Hyperphosphatemia:
  • Occurs late in chronic kidney disease.
  • Treated with dietary restriction, dietary phosphate binders and calcium carbonate.
• Hypocalcaemia:
  • Prescribe calcium supplements, with or without calcitriol.
• Hyperparathyroidism:
  • Reduce hyperphosphataemia by diet and phosphate binders.
  • Prescribe 1,25-dihydroxycholecalciferol and maintain a normal calcium level.
  • Secondary hyperparathyroidism starts early in chronic renal failure and is difficult to treat when it becomes established.
  • Secondary hyperparathyroidism may lead to tertiary hyperparathyroidism if not treated effectively.
• Malnutrition:
  • Must be avoided, although protein restriction can slow progression of renal failure.
  • Restriction of dietary protein slows the progress of glomerulosclerosis in residual nephrons in animal experimental models.
  • There remains controversy as to the benefits of protein restriction for treatment. Although patients are advised against high-protein diets, low-protein diets are not usually recommended and the emphasis is to maintain good nutrition.

Prognosis

• Much of the damage caused by chronic kidney disease occurs early, when interventions may be much more effective.
• Patients with chronic kidney disease usually progress to end-stage renal disease. The rate of progression depends on the underlying diagnosis, on the successful implementation of secondary preventative measures, and on the individual patient.
• Patients on chronic dialysis have a high incidence of morbidity and mortality. Patients with ESRD (end-stage renal disease) who undergo renal transplantation survive longer than those on chronic dialysis.
• Cardiovascular disease is the most common cause of death in patients with chronic kidney disease. Cardiovascular mortality is doubled in patients with a GFR below 70 ml/minute.

Prevention

Early diagnosis and good control of potential causes, e.g. diabetes, hypertension and urinary tract obstruction.

Quality and Outcome Framework

Chronic kidney disease was included in the Quality and Outcome Framework of the GP Contract in April 2006.
The following indicators were added:

• Records
  • CKD1: The practice can produce a register of patients aged 18 years and over with CKD (US National Kidney Foundation: Stage 3 to 5 CKD).
• Initial Management
  • CKD2: The percentage of patients on the CKD register whose notes have a record of blood pressure in the previous 15 months.
• Ongoing Management
  • CKD3: The percentage of patients on the CKD register in whom the last blood pressure reading, measured in the previous 15 months, is 140/85 mmHg or less
  • CKD4: The percentage of patients on the CKD register with hypertension who are treated with an angiotensin converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) (unless a contraindication or side effects are recorded).

Much of the rational for these indicators is enshrined in Part Two of the National Service Framework for Renal Services - Chronic Kidney Disease, Acute Renal Failure and End of Life Care.²

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Document references

1. Royal College of General Practitioners; Introducing eGFR- Promoting good CKD management
2. Department of Health Feb 2005; National Service Framework for Renal Services - Part Two: Chronic kidney disease, acute renal failure and end of life care
3. The Renal Association; UK Guidelines for the management of Chronic Kidney Disease. June 2005.
4. Levey AS, Bosch JP, Lewis JB, et al; A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999 Mar 16;130(6):461-70. [abstract]
5. More about eGFR; UK CKD Guide Renal Association 2007
6. Mitra PK, Tasker PR, Ell MS; Chronic kidney disease. BMJ. 2007 Jun 16;334(7606):1273.

Source : http://www.patient.co.uk/showdoc/40025274/

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WHO Issues Patient Care Checklist for Influenza A (H1N1)

The World Health Organization (WHO) has developed a new patient care checklist for hospital staff worldwide to use when treating suspected or confirmed cases of influenza A (H1N1). It is not intended to be comprehensive or to replace routine care or clinical judgment, but all hospitals are encouraged to use the checklist and to modify it as appropriate for their local practice setting.

"The WHO Patient Care Checklist: new influenza A (H1N1) is intended for use by hospital staff treating a patient with a medically suspected or confirmed case of new influenza A (H1N1)," the checklist document states. "This checklist combines two aspects of care: i) clinical management of the individual patient and ii) infection control measures to limit the spread of new influenza A (H1N1)."

Some specific recommendations:

• When the patient arrives at triage, those with flu-like symptoms should be directed to a designated waiting area and given instruction and educational materials regarding respiratory hygiene and cough etiquette (cover mouth and nose with a tissue when coughing or sneezing, discard tissue in a bin with a lid, and then clean hands). Patients who can tolerate it should wear a medical or surgical mask, which should also be worn during patient transport and transfer.
• When the patient is first evaluated, respiratory rate should be recorded for 1 full minute, as well as oxygen saturation when available. Senior care staff should be notified and consulted if respiratory rate is high or oxygen saturation is under 90%. History should document flu-like symptoms, date of onset, travel, exposure to persons with flu-like symptoms, and comorbid conditions, and alternative or additional diagnoses should be considered.
• Specialized diagnostic tests, such as reverse transcriptase polymerase chain reaction, may be indicated. When taking respiratory samples, healthcare personnel should wear a medical or surgical mask, eye protection, and gloves. Specimens should be correctly labeled and sent with biohazard precautions in compliance with local regulations. Suspected cases of H1N1 infection should be reported to the local authorities.
• Before the patient arrives at the isolation room or cohort, restricted entry and infection control signs should be posted. When available, dedicated patient equipment should be provided. Patients in the cohort area should be separated by at least 1 meter (3.3 feet). The local hospital protocol should be implemented for frequent linen and surface cleaning.
• Before a healthcare staff member or visitor enters an isolation room or cohort, they should put on a medical or surgical mask and clean their hands by hand rubbing with an alcohol-based hand rub formulation (preferred unless hands are visibly soiled) or by hand washing with soap and water.
• Before any exposure to a patient with known or suspected H1N1 influenza infection, healthcare staff should don a medical or surgical mask and clean their hands. When there is risk for exposure to body fluids or splashes, eye protection, gown, and gloves should also be worn. Personal or dedicated patient equipment should be cleaned and disinfected. Between patients, staff should change their gloves and clean their hands.
• When aerosol-generating procedures, such as intubation, bronchoscopy, cardiopulmonary resuscitation, or suctioning are being performed, only those staff essential to the procedure should be allowed access. The procedure should be done in an adequately ventilated room. A gown, particulate respirator (if available; eg, EU FFP2, US NIOSH-certified N95), eye protection, and gloves should be worn.
• Before a healthcare staff member or visitor leaves an isolation room or cohort, they should remove their gloves, gown, mask, eye protection, and any other personal protective equipment and discard disposable supplies according to hospital protocol. Hands should be cleaned, and dedicated patient equipment and personal equipment used by the patient should be cleaned and disinfected. Viral-contaminated waste should be disposed of as clinical waste.
• Alternative or additional diagnoses should be considered in patients with known or suspected H1N1 infection.
• Supportive treatment for patients with H1N1 infection should be similar to that for any influenza patient. Supplemental oxygen should be given as needed to maintain oxygen saturation above 90%, as well as to patients with increased respiratory rate if monitoring oxygen saturation is not feasible. For patients younger than 18 years, paracetamol or acetaminophen is recommended as an antipyretic. Patients with evidence of pneumonia or secondary bacterial infection should receive appropriate antibiotics. Use of the antiviral drugs oseltamivir or zanamivir should be considered after weighing contraindications and potential drug interactions.
• Before a patient with a confirmed or suspected case of H1N1 influenza infection is discharged from hospital, the patient and/or caregiver should be educated and given materials regarding respiratory hygiene and cough etiquette and counseled regarding home isolation, infection control, and limiting social contact. Patient contact information should be recorded.
• After discharge, dedicated patient equipment should be discarded or cleaned and disinfected according to the hospital protocol, linen should be changed and laundered without shaking, surfaces should be cleaned according to the hospital per local protocol, and viral-contaminated waste should be disposed of as clinical waste.

"Staff can use this checklist in a variety of ways — ticking the boxes is optional," the WHO document states. "The objective is to ensure that no critical patient care items are missed during or immediately following care. The checklist can be used as part of the patient's clinical record; reproduced as wall posters for hospitals or clinics; or printed up as cards for staff members to carry around with them."

The checklist is currently being assessed and updated to improve usability, and WHO plans to post the updated version on its Web site.

Source : http://www.medscape.com/viewarticle/705527?src=mpnews&spon=34&uac=133298AG

High-Dose Intravenous Esomeprazole May Reduce Recurrent Peptic Ulcer Bleeding

High-dose intravenous esomeprazole given after successful endoscopic therapy may reduce recurrent bleeding in high-risk patients with peptic ulcer, according to the results of a randomized controlled trial reported in the February 17 Online First issue of the Annals of Internal Medicine.

"Use of proton-pump inhibitors in the management of peptic ulcer bleeding is controversial because of discrepant results reported in different ethnic groups," write Joseph J.Y. Sung, MD, from the Chinese University of Hong Kong in China, and colleagues from the Peptic Ulcer Bleed Study Group. "Profound and sustained acid suppression, as achieved with high-dose intravenous proton-pump inhibitors (PPIs), is thought to improve outcomes by clot stabilization at higher gastric pH."

The goal of this study was to determine whether intravenous esomeprazole was more effective than placebo at preventing recurrent peptic ulcer bleeding in a multiethnic patient sample.

Between October 2005 and December 2007, patients 18 years or older with peptic ulcer bleeding were enrolled from 91 hospital emergency departments in 16 countries. Participants had bleeding from a single gastric or duodenal ulcer with high-risk stigmata, and all had successful endoscopic hemostasis before randomization. Participants, clinicians, and investigators were blinded as to group assignment.

Through computer-generated randomization, participants were assigned to receive either esomeprazole, 80-mg intravenous bolus followed by 8-mg/hour infusion for 72 hours, or matching placebo. After infusion, patients in both groups were given oral esomeprazole, 40 mg/day, for 27 days. The main outcome of the study was rate of clinically significant recurrent bleeding within 72 hours, and other outcomes were recurrent bleeding within 7 and 30 days, death, surgery, endoscopic re-treatment, blood transfusions, hospitalization, and safety.

Of 767 participants who were randomly assigned, data were available for an intent-to-treat analysis in 764, of whom 375 were in the esomeprazole group and 389 in the placebo group.

Recurrent bleeding within 72 hours occurred in 22 of 375 patients receiving intravenous esomeprazole vs 40 of 389 receiving placebo (5.9% vs 10.3%; 95% confidence interval [CI] of difference, 0.6% - 8.3%; P = .026). At 7 days and 30 days, the difference in bleeding recurrence was still significant (P = .010).

Endoscopic re-treatment was significantly less in the esomeprazole group (6.4% vs 11.6%; 95% CI of difference, 1.1% - 9.2%; P = .012). Compared with placebo, there was also a nonsignificant trend for lower rates of surgery (2.7% vs 5.4%) and all-cause mortality (0.8% vs 2.1%).

In both groups, serious adverse events (AEs) were reported in approximately 10% and nonserious AEs in approximately 40% of patients.

"High-dose intravenous esomeprazole given after successful endoscopic therapy to patients with high-risk peptic ulcer bleeding reduced recurrent bleeding at 72 hours and had sustained clinical benefits for up to 30 days," the study authors write. "This was accompanied by a reduction in endoscopic re-treatment, blood transfusions, and hospital stays because of recurrent bleeding in the esomeprazole group compared with the placebo group."

Limitations of this study include endoscopic therapy not completely standardized; some patients receiving epinephrine injection, thermal coagulation, or hemoclips alone, whereas others receiving combination therapy; slight baseline imbalance with fewer Forrest class Ia ulcers in the esomeprazole group; and insufficient power to detect differences in low mortality rates.

"We believe that this is the first international trial to provide high-quality evidence supporting the use of high-dose intravenous esomeprazole as adjuvant therapy to endoscopic therapy for patients with high-risk endoscopic lesions and peptic ulcer bleeding in a predominantly Caucasian population," the study authors conclude. "In our view, the data indicate that the efficacy of PPIs [proton pump inhibitors] in preventing recurrent peptic ulcer bleeding is not race-specific and should be universally applied."

Medscape obtained independent commentary on this study from Akihiro Tajima, MD, PhD (assistant professor), Tadahito Shimada, MD, PhD (associate professor), and Hideyuki Hiraishi, MD,, PhD (chief and professor), all from the Department of Gastroenterology, Dokkyo Medical University in Mibu, Tochigi, Japan.

They told Medscape that the results suggest that early treatment within the first 3 days is important for ulcer cure but that various methods for endoscopic hemostasis might have some different effects on ulcer healing in the esomeprazole and placebo groups.

"Intravenous esomeprazole for prevention of recurrent peptic ulcer bleeding would reduce unnecessary repeated endoscopy," they said. "Infusion-site reactions were more common in the esomeprazole group. Dose reduction might be considered in the continuous infusion phase."

Regarding future research, they suggest that regular-dose esomeprazole, instead of placebo, should be used as a control therapy to show the actual effect of high-dose esomeprazole on the reduction of recurrent bleeding.

"The effect of esomeprazole upon peptic ulcer may be different among several races," they said. "Fibrosis around ulcer scars might be obvious in repeated peptic ulcers, suggesting some difficulties in endoscopic hemostasis. From at least these two viewpoints, tailor made therapy, such as a different dose of esomeprazole, for peptic ulcers needs to be [tested with] additional research."

Source : http://www.medscape.com/viewarticle/588961

ASMBS 2009: Elderly Obese Patients Benefit From Weight Loss Surgery

Patients who are older than 65 years fare no differently from their younger counterparts after weight loss surgery, suggesting older age is not a risk factor for complications or mortality in bariatric surgery, a study presented here at the American Society for Metabolic and Bariatric Surgery 26th Annual Meeting shows.

The findings refute previous data that indicated mortality was greater in the elderly after gastric bypass surgery, according to Joseph Kuhn, MD, director of clinical research, Department of Surgery, Baylor University Medical Center, Dallas, Texas.

"A few reports that were released years ago had shown a higher mortality rate occurring with this surgery in patients over 65 [years old]," explained Dr. Kuhn, the study's principal investigator. "Most of those procedures were open gastric bypass surgeries...only a smattering of them were laparoscop[ic], and most of those were in the learning curve. Modern programs in laparoscopic surgery mean most patients go home the very next day, even with patients who are older than 65."

Dr. Kuhn and coinvestigators prospectively followed 1753 patients who underwent bariatric surgery between January 2005 and July 2008 at their center and who had at least 6 weeks of postoperative follow-up data.

There were 153 patients who were older than 65 years. They had a less favorable operative risk profile compared with 1600 younger patients who also were followed up. Specifically, older patients had an increased incidence of sleep apnea (46% vs 33%), diabetes mellitus (62% vs 31%), and hypertension (83% vs 57%). The older patients ranged in age from 65 to 77 years and had a mean body mass index of 45 kg/m², whereas younger patients ranged in age from 18 to 64 years and had a mean body mass index of 47 kg/m².

Despite their poorer health status, operative outcomes for patients older than 65 years were similar to those for patients younger than 65 years. Operative time was 70 minutes vs 65 minutes, length of stay was 1.6 days vs 1.3 days, and the 30-day readmission rate was 5.2% vs 7.0%.

Furthermore, complication rates did not significantly differ between older and younger patients. Among seniors, there was postoperative bleeding in 0.6% of patients, pulmonary complications in 1.9%, cardiac complications in 1.9%, wound complications in 1.9%, and stricture complications in 1.2%; there were no deaths.

The percentage of excess body weight loss (% EBWL) in patients who had gastric bypass surgery was not significantly different between the older and younger patients at 12 months (60.4% EBWL vs 71.9% EBWL).

Among patients who had undergone gastric banding, there was comparable weight loss in older and younger patients at the 12-month mark (29.9% EBWL vs 35.8% EBWL) and at the 24-month mark (45.3% EBWL vs 33.4% EBWL).

"In contrast to the countless operations that are performed on patients over the age of 65 [years —] like hip replacements, various kinds of cancer surgeries, liver and lung resections — typically as surgeons we don't hesitate for a second in performing those operations," said Dr. Kuhn.

"One of the obstacles is the anxiety of [perceived] risk," said Dr. Kuhn. "The patients are definitely in need of about 100 pounds of weight loss. They are sicker, with more comorbid problems."

Bruce Wolfe, MD, FACS, a member of the executive council of the American Society for Metabolic and Bariatric Surgery and a professor of surgery at Oregon Health and Science University in Portland, concurred that advancing age had been identified as a risk factor for adverse outcomes following gastric bypass surgery and other bariatric procedures in older analyses.

"The notion that the surgery should be performed infrequently, if at all, in progressively older, severely obese patients has had some basis," said Dr. Wolfe. "What is important is that we look at the current status of surgery. There have been a number of improvements reported overall in the outcomes of bariatric surgery in various databases that have not found advancing age [to be a risk factor for adverse outcome after the mid-60s]."

The study's findings show that discouraging the surgery in patients who are not much older than 65 years needs to be reexamined, said Dr. Wolfe, noting that a limitation of the study was that the oldest patient in the study was aged 77 years.

"[Surgery in patients] who are just older than 65 was shown to be safe, but the safety of patients in their late 70s was not addressed," he said.

Dr. Kuhn has disclosed no relevant financial relationships. Dr. Wolfe is a consultant for Ethicon Endo-Surger Inc and Allergan Inc and is an investigator for EnteroMedics Inc.

American Society for Metabolic and Bariatric Surgery (ASMBS) 26th Annual Meeting: Abstract PL-207. Presented June 25, 2009.

Source : http://www.medscape.com/viewarticle/705055?src=mpnews

Vasopressin and Epinephrine vs. Epinephrine Alone in Cardiopulmonary Resuscitation

Description

The goal of the trial was to evaluate treatment with vasopressin and epinephrine compared with epinephrine alone among patients with an out-of-hospital cardiac arrest.

Hypothesis

Vasopressin and epinephrine will be more effective in improving survival.

Drugs/Procedures Used

Patients with cardiac arrest were randomized to 40 IU vasopressin and 1 mg epinephrine (n =1,442) versus placebo and 1 mg epinephrine (n = 1,452). Study drugs were re-administered if there was no return in spontaneous circulation within 3 minutes. Defibrillation was attempted up to 3 times before randomization among patients who presented with ventricular fibrillation (VF).

Principal Findings

Overall, 2,956 patients underwent randomization. There were 62 patients excluded after randomization: 26 did not provide informed consent, 29 had traumatic cardiac arrest, and 7 did not meet other inclusion criteria. Baseline characteristics were well-matched, except that there were more men in the vasopressin and epinephrine group (75.4% vs. 71.7%, p = 0.03). The initial cardiac rhythm was VF in 9.2% versus 9.3%, pulseless electrical activity in 7.7% versus 8.3%, and asystole in 83.1% versus 82.4%, respectively. The time to arrival of emergency medical technicians was 7.2 minutes versus 6.8 minutes, and the total duration of advanced cardiac life support was 38.0 minutes versus 37.6 minutes, respectively.

The primary outcome, survival to hospital admission, occurred in 20.7% of the combination treatment group compared with 21.3% of the epinephrine alone group (p = 0.69). Return of spontaneous circulation occurred in 28.6% versus 29.5% (p = 0.62), survival to hospital discharge occurred in 1.7% versus 2.3% (p = 0.24), 1-year survival occurred in 1.3% versus 2.1% (p = 0.09), and good neurological recovery at hospital discharge occurred in 37.5% versus 51.5% (p = 0.29), respectively, for combination treatment versus epinephrine alone. Among patients who presented with pulseless electrical activity, survival to hospital discharge was 0% versus 5.8% (p = 0.02), respectively. There was no difference in this outcome among patients with VF or asystole.

Interpretation

The prognosis among patients who suffer an out-of-hospital cardiac arrest, especially asystole, remains grim. The combination of vasopressin and epinephrine is not superior to epinephrine alone in improving clinical outcomes. Specifically, there was no difference in survival to hospital admission or discharge, return in spontaneous circulation, good neurological recovery, or 1-year survival between the treatment groups. The finding of decreased survival to hospital discharge among the combination treatment group should only be considered hypothesis generating.

Conditions

• Arrhythmias / Ventricular fibrillation

Therapies

• Medical

Study Design

Randomized. Blinded. Parallel. Stratified.

Patients Enrolled: 2,956

Mean Follow-Up: 1 year

Mean Patient Age: 62 years

% Female: 27

Primary Endpoints

Survival to hospital admission. Survival was defined as a palpable pulse and measurable blood pressure upon arrival to an intensive care unit.

Secondary Endpoints

Return of spontaneous circulation

Survival to hospital discharge

Good neurological recovery

Survival at 1 year

Patient Population

Adult patients with a cardiac arrest due to VF, pulseless electrical activity, or asystole

Exclusions:

Age less than 18 years

Successful defibrillation without the need for vasopressor therapy

Traumatic cardiac arrest

Known pregnancy

Documented terminal illness

Do-not-resuscitate order

Sign of an irreversible cardiac arrest

Source : http://www.medscape.com/viewarticle/582270