Alon Grossman

The Safety of Intravenous Iron Preparations: Systematic Review and Meta-analysis

OBJECTIVE To amass all available evidence regarding the safety of intravenous (IV) iron preparations to provide a true balance of efficacy and safety. METHODS Systematic review and meta-analysis of all randomized clinical trials comparing IV iron to another comparator. All electronic databases until January 1, 2014, were reviewed. Primary outcome was occurrence of severe adverse events (SAEs). Secondary outcomes included all-cause mortality and other adverse events (AEs). Subgroup analysis was performed on the basis of type of IV iron, comparator, treated condition, and system involved. RESULTS A total of 103 trials published between 1965 through 2013 were included. A total of 10,390 patients were treated with IV iron compared with 4044 patients treated with oral iron, 1329 with no iron, 3335 with placebo, and 155 with intramuscular iron. There was no increased risk of SAEs with IV iron (relative risk [RR], 1.04; 95% CI, 0.93-1.17; I(2)=9%). Subgroup analysis revealed a decreased rate of SAEs when IV iron was used to treat heart failure (RR, 0.45; 95% CI, 0.29-0.70; I(2)=0%). Severe infusion reactions were more common with IV iron (RR, 2.47; 95% CI, 1.43-4.28; I(2)=0%). There was no increased risk of infections with IV iron. Gastrointestinal AEs were reduced with IV iron. CONCLUSION Intravenous iron therapy is not associated with an increased risk of SAEs or infections. Infusion reactions are more pronounced with IV iron.

Vasopressors for the Treatment of Septic Shock: Systematic Review and Meta-Analysis

Objective International guidelines recommend dopamine or norepinephrine as first-line vasopressor agents in septic shock. Phenylephrine, epinephrine, vasopressin and terlipressin are considered second-line agents. Our objective was to assess the evidence for the efficiency and safety of all vasopressors in septic shock. Methods Systematic review and meta-analysis. We searched electronic database of MEDLINE, CENTRAL, LILACS and conference proceedings up to June 2014. We included randomized controlled trials comparing different vasopressors for the treatment of adult patients with septic shock. Primary outcome was all-cause mortality. Other clinical and hemodynamic measurements were extracted as secondary outcomes. Risk ratios (RR) and mean differences with 95% confidence intervals (CI) were pooled. Results Thirty-two trials (3,544 patients) were included. Compared to dopamine (866 patients, 450 events), norepinephrine (832 patients, 376 events) was associated with decreased all-cause mortality, RR 0.89 (95% CI 0.81-0.98), corresponding to an absolute risk reduction of 11% and number needed to treat of 9. Norepinephrine was associated with lower risk for major adverse events and cardiac arrhythmias compared to dopamine. No other mortality benefit was demonstrated for the comparisons of norepinephrine to epinephrine, phenylephrine and vasopressin / terlipressin. Hemodynamic data were similar between the different vasopressors, with some advantage for norepinephrine in central venous pressure, urinary output and blood lactate levels. Conclusions Evidence suggests a survival benefit, better hemodynamic profile and reduced adverse events rate for norepinephrine over dopamine. Norepinephrine should be regarded as the first line vasopressor in the treatment of septic shock.

Inter-Arm Blood Pressure Differences in Young, Healthy Patients

The prevalence and magnitude of inter‐arm BP difference (IAD) in young healthy patients is not well characterized. Flight academy applicants and designated aviators undergo annual evaluation that includes blood pressure (BP) measurement on both arms. All BP measurements performed from January 1, 2012, to April 30, 2012, were recorded and IAD was calculated. Results were compared between patients in whom BP was initially measured in the right arm (group 1), those in whom BP was initially measured in the left arm (group 2), and those in whom the arm in which BP was initially measured was not recorded (group 3). A total of 877 healthy patients had BP measured during the study period. In the entire group, mean systolic BP was the same in both arms. Absolute IAD was 5.6±5.5 mm Hg for systolic and 4.7±4.5 mm Hg for diastolic BP. IAD >10 mm Hg was recorded in 111 (12.6%) and 77 (8.8%) patients for systolic and diastolic BP, respectively. IAD was the same in the 3 groups and was unrelated to age, body mass index, and heart rate, but was related to systolic BP. IAD is common in young healthy patients, is not dependent on which arm was measured first, and unrelated to age, body mass index, and heart rate.

[18F]FDG-PET/CT for the diagnosis of patients with fever of unknown origin

BACKGROUND AND AIMS The diagnosis of patients with fever of unknown origin (FUO) remains a challenging medical problem. We aimed to assess the diagnostic contribution of 18-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET)/computed tomography (CT) for the evaluation of FUO. METHODS We performed a 4-year retrospective single-center study of all hospitalized patients that underwent FDG-PET/CT for evaluation of FUO. The final diagnosis of the febrile disease was based on clinical, microbiological, radiological and pathological data available at the final follow-up. Predictors for a contributory exam were sought. RESULTS One hundred and twelve patients underwent FDG-PET/CT for the investigation of FUO in the years 2008-2012 and were included in the study. A final diagnosis was determined in 83 patients (74%) and included: infectious disease in 49 patients (43%), non-infectious inflammatory disease in 17 patients (16%), malignancies in 15 patients (14%), other diagnoses in 2 patients (1.7%), FUO resolved with no diagnosis and no evidence of disease during a 6-month follow-up in 23 patients (20%), and death with fever and with no diagnosis in 6 patients (5%). Seventy-four FDG-PET/CT studies (66%) were considered clinically helpful and contributory to diagnosis (46% positive contributory value and 20.5% contributory to exclusion of diagnosis). PET/CT had a sensitivity of 72.2%, a specificity of 57.5%, a positive predictive value (PPV) of 74.2% and a negative predictive value (NPV) of 53.5%. On multivariable analysis, significant predictors of a positive PET/CT contributory to diagnosis were a short duration of fever and male gender. CONCLUSIONS PET/CT is an important diagnostic tool for patients with FUO.

Subclinical Thyroid Disease and Mortality in the Elderly: A Retrospective Cohort Study

OBJECTIVE The association between subclinical hypothyroidism and hyperthyroidism and mortality in the elderly is poorly defined. This study was designed to evaluate the association between subclinical hypothyroidism and subclinical hyperthyroidism and mortality in the elderly and to define the thyroid-stimulating hormone values associated with excess mortality in the elderly. METHODS We performed a retrospective cohort study with a review of a computerized database of a large health care organization. Patients aged more than 65 years evaluated in the years 2002 to 2012 with documented normal free T4 values were included in the analysis. All cases of known thyroid disease or cases in which thyroid medications were dispensed were excluded. Analysis was performed only on individuals who were not treated for hyperthyroidism or hypothyroidism during the follow-up period. Subjects were divided into 3 groups based on thyroid-stimulating hormone values: normal (normal thyroid-stimulating hormone), subclinical hypothyroidism (thyroid-stimulating hormone >4.2 mIU/L), and subclinical hyperthyroidism (thyroid-stimulating hormone <0.35 mIU/L). All-cause mortality hazard ratio (HR) was compared among the 3 groups, and a subanalysis according to thyroid-stimulating hormone values was performed in those with subclinical hypothyroidism and subclinical hyperthyroidism. RESULTS A final analysis was performed on 17,440 individuals with subclinical thyroid disease (538 with subclinical hyperthyroidism [3.1%], 1956 with subclinical hypothyroidism [11.2%], 14,946 normal cases [85.7%], average age of 83 years, 10,289 were women) who were followed up for 10 years. Both subclinical hypothyroidism (HR, 1.75; confidence interval [CI], 1.63-1.88) and subclinical hyperthyroidism (HR, 2.33; CI, 2.08-2.63) were associated with significantly increased mortality, and this association persisted on multivariate analysis (subclinical hypothyroidism HR, 1.68; CI, 1.56-1.8, subclinical hyperthyroidism HR, 1.93; CI, 1.7-2.17). Crude mortality was elevated at 1, 2, and 5 years, but this association seemed to decrease as time from initial analysis increased (most significant association at 1 year). Thyroid-stimulating hormone values greater than 6.38 mIU/L were associated with the highest mortality in those with subclinical hypothyroidism after multivariate adjustment (HR, 1.708; CI, 1.38-2.12), whereas in subclinical hyperthyroidism, no threshold for increased mortality was identified. Mortality was higher. CONCLUSIONS Both subclinical hypothyroidism and subclinical hyperthyroidism are associated with increased mortality in the elderly. A threshold thyroid-stimulating hormone value (>6.35 mIU/L) exists for increased mortality in subclinical hypothyroidism, but not in subclinical hyperthyroidism.

Drug induced hypertension--An unappreciated cause of secondary hypertension.

Most patients with hypertension have essential hypertension or well-known forms of secondary hypertension, such as renal disease, renal artery stenosis, or common endocrine diseases (hyperaldosteronism or pheochromocytoma). Physicians are less aware of drug induced hypertension. A variety of therapeutic agents or chemical substances may increase blood pressure. When a patient with well controlled hypertension is presented with acute blood pressure elevation, use of drug or chemical substance which increases blood pressure should be suspected. Drug-induced blood pressure increases are usually minor and short-lived, although rare hypertensive emergencies associated with use of certain drugs have been reported. Careful evaluation of prescription and non-prescription medications is crucial in the evaluation of the hypertensive individual and may obviate the need for expensive and unnecessary evaluations. Discontinuation of the offending agent will usually achieve adequate blood pressure control. When use of a chemical agent which increases blood pressure is mandatory, anti-hypertensive therapy may facilitate continued use of this agent. We summarize the therapeutic agents or chemical substances that elevate blood pressure and their mechanisms of action.

Crush Syndrome: Saving More Lives in Disasters: Lessons Learned From the Early-Response Phase in Haiti

T he Israel Defense Forces Medical Corps Field Hospital was fully operational 89 hours after the Haiti earthquake in January 2010. In earthquake scenarios, crush injuries are a major cause of death. The incidence of crush syndrome can be as high as 25% in earthquake victims. Acute renal failure (ARF), a complication of crush syndrome that is commonly encountered in the first days following earthquakes, has an excellent outcome when renal replacement treatment (RRT) is available. The incidence of ARF related to crush syndrome depends on the intensity of the earthquake and the amount of time spent under rubble, and ranges from 0.5% to 25%. More than half of those with renal failure will require RRT.

Interventricular Septum Thickness Predicts Future Systolic Hypertension in Young Healthy Pilots

Left ventricular hypertrophy (LVH) has been associated with hypertension, although debate exists as to whether LVH is caused by elevated blood pressure (BP) or is a risk factor for its development. The present study evaluates the association between left ventricular structure and the development of hypertension in a young healthy population. We followed young healthy Israeli Air Force aviators from initial echocardiography at the start of their military service to a mean of 7.5±3.0 years. Data collection included annual BP measurements, height, weight, smoking habits, and lipid profile. We monitored 500 Air Force men with a mean age of 20.5±3.3 (range, 17−40) years and baseline BP of 125±13/74±8 mmHg. Systolic BP during follow-up was associated with baseline systolic BP, interventricular septum (IVS) thickness, and ejection fraction, whereas diastolic BP was associated only with baseline diastolic BP and body mass index. The probability that the systolic BP during follow-up would be higher than the median was twice that in those with an IVS thickness greater than the median. In conclusion, IVS thickening was associated with long-term elevation of systolic BP. Therefore, it seems that IVS thickening is not merely a result of long-term BP elevation, but may predict the development of systolic hypertension. (Hypertens Res 2008; 31: 15−20)

Atypical HUS due to factor H antibodies in an adult patient successfully treated with eculizumab

Abstract Background: Anti-complement factor H (CFH) antibodies is an extremely rare cause of atypical hemolytic uremic syndrome (aHUS) in adults, with less than 10 cases reported thus far. Although infectious diarrhea is a common inciting trigger for aHUS episode, there are no reports of an association with inflammatory bowel disease. Eculizumab is an emerging treatment for aHUS. Eculizumab has not been reported thus far to be given for aHUS due to anti-CFH antibodies. We report here for the first time on an adult patient with ulcerative colitis (UC) who developed aHUS due to anti-CFH antibodies, presented with decreased serum levels of both C3 and C4. She had an excellent response to treatment with eculizumab. Case presentation: A 27-year-old Caucasian woman, who suffered from steroid-dependent UC, was admitted with microangiopathic hemolytic anemia and acute kidney injury with nephrotic syndrome. ADAMTS 13 was normal and comprehensive workout for secondary causes of HUS was negative. Both serum complement level of C3 and C4 were low. Kidney biopsy was compatible with the diagnosis of HUS with negative immunofluorescence. Because of only partial response to plasma exchange and high dose steroids, eculizumab was commenced. After two weeks signs of microangiopathy subsided, and kidney function began to recover. Few months after the diagnosis, a complement components investigation revealed antibodies against CFH at high titer of 2000 arbitrary units. Today her creatinine is stable with no proteinuria and no signs of HUS.

Back symptoms in aviators flying different aircraft.

INTRODUCTION Back pain is a common complaint among military aviators of various aircraft. We attempted to define the epidemiologic characteristics of this complaint in military aviators of the Israeli Air Force. METHODS Aviators of various aircraft (fighter, attack helicopter, utility helicopter, and transport and cargo) completed 566 questionnaires. The questionnaires included various demographic variables as well as questions specifically addressing type of aircraft, location, and severity of pain. Questionnaires were analyzed according to aircraft type, weekly and total number of flight hours. RESULTS Back pain was significantly more common among utility and attack helicopter pilots. Compared with only 64.02% of fighter pilots, 89.38% of utility and 74.55% of attack helicopter pilots reported some degree of back pain. Cervical region pain was more common among fighter pilots (47.2%) and utility helicopter pilots (47.3%) compared with attack helicopter (36.4%) and transport (22.3%) pilots. Cervical region pain of moderate-severe degree was more common among utility helicopter pilots (7.1%). Mid and low back pain at all degrees of severity were more common among helicopter pilots. A significant proportion of subjects suffered from pain in multiple regions, particularly among utility helicopter pilots (32.74%). Severity of pain was graded higher in all three regions (cervical, mid, and lower back) in utility helicopter pilots. CONCLUSIONS Utility helicopter pilots have more prevalent and more severe back pain than pilots of other platforms. Yet, it is difficult to make a clear association between type of aircraft and the region of back pain.