Medical Student H&Ps: Do You Have to Observe Them All At Once?

OBJECTIVES: Direct observation of medical students' history and physical examination (H&P) skills by attendings is essential in ensuring trainees' competence. This study compared whether partial observations by multiple pediatric attendings across various clinical encounters versus a full observation by one attending affected students' performance on the pediatric Objective Structured Clinical Examination (OSCE) and the Year 3 Clinical Performance Examination (CPX3). METHODS: For the 2013-2014 and 2014-2015 academic years, 323 medical students submitted either H&P checklists completed by one attending observing an entire H&P (full observations) versus multiple attendings observing portions of the H&P (partial observations). The full and partial observation groups were compared by their pediatric OSCE and CPX3 performance. RESULTS: Students submitting full observations (n = 185) versus partial observations (n = 138) revealed no difference in OSCE (3.10 vs 3.10, P = 0.98) or CPX3 scores (74.49 vs 75.31, P = 0.18). Students submitting checklists by clerkship midpoint performed better on the OSCE (3.11 vs 2.88, P = 0.001) and CPX3 (75.00 vs 72.25, P = 0.03). CONCLUSIONS: Partial versus full observations of students' H&P skills have no effect on standardized clinical examination performance, and clerkships should consider using partial observations of students for efficient assessments. Promptness of checklist submission also may be an indicator of examination performance.

Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial.

BACKGROUND: For children with sickle cell anaemia and high transcranial doppler (TCD) flow velocities, regular blood transfusions can effectively prevent primary stroke, but must be continued indefinitely. The efficacy of hydroxycarbamide (hydroxyurea) in this setting is unknown; we performed the TWiTCH trial to compare hydroxyurea with standard transfusions. METHODS: TWiTCH was a multicentre, phase 3, randomised, open-label, non-inferiority trial done at 26 paediatric hospitals and health centres in the USA and Canada. We enrolled children with sickle cell anaemia who were aged 4-16 years and had abnormal TCD flow velocities (≥ 200 cm/s) but no severe vasculopathy. After screening, eligible participants were randomly assigned 1:1 to continue standard transfusions (standard group) or hydroxycarbamide (alternative group). Randomisation was done at a central site, stratified by site with a block size of four, and an adaptive randomisation scheme was used to balance the covariates of baseline age and TCD velocity. The study was open-label, but TCD examinations were read centrally by observers masked to treatment assignment and previous TCD results. Participants assigned to standard treatment continued to receive monthly transfusions to maintain 30% sickle haemoglobin or lower, while those assigned to the alternative treatment started oral hydroxycarbamide at 20 mg/kg per day, which was escalated to each participant's maximum tolerated dose. The treatment period lasted 24 months from randomisation. The primary study endpoint was the 24 month TCD velocity calculated from a general linear mixed model, with the non-inferiority margin set at 15 cm/s. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of assigned treatment. This study is registered with ClinicalTrials.gov, number NCT01425307. FINDINGS: Between Sept 20, 2011, and April 17, 2013, 159 patients consented and enrolled in TWiTCH. 121 participants passed screening and were then randomly assigned to treatment (61 to transfusions and 60 to hydroxycarbamide). At the first scheduled interim analysis, non-inferiority was shown and the sponsor terminated the study. Final model-based TCD velocities were 143 cm/s (95% CI 140-146) in children who received standard transfusions and 138 cm/s (135-142) in those who received hydroxycarbamide, with a difference of 4·54 (0·10-8·98). Non-inferiority (p=8·82 × 10(-16)) and post-hoc superiority (p=0·023) were met. Of 29 new neurological events adjudicated centrally by masked reviewers, no strokes were identified, but three transient ischaemic attacks occurred in each group. Magnetic resonance brain imaging and angiography (MRI and MRA) at exit showed no new cerebral infarcts in either treatment group, but worsened vasculopathy in one participant who received standard transfusions. 23 severe adverse events in nine (15%) patients were reported for hydroxycarbamide and ten serious adverse events in six (10%) patients were reported for standard transfusions. The most common serious adverse event in both groups was vaso-occlusive pain (11 events in five [8%] patients with hydroxycarbamide and three events in one [2%] patient for transfusions). INTERPRETATION: For high-risk children with sickle cell anaemia and abnormal TCD velocities who have received at least 1 year of transfusions, and have no MRA-defined severe vasculopathy, hydroxycarbamide treatment can substitute for chronic transfusions to maintain TCD velocities and help to prevent primary stroke. FUNDING: National Heart, Lung, and Blood Institute, National Institutes of Health.

Magnetic resonance imaging/angiography and transcranial Doppler velocities in sickle cell anemia: results from the SWiTCH trial.

The Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) trial compared standard (transfusions/chelation) to alternative (hydroxyurea/phlebotomy) treatment to prevent recurrent stroke and manage iron overload in children chronically transfused over 7 years before enrollment. Standardized brain magnetic resonance imaging/magnetic resonance angiography (MRA) and transcranial Doppler (TCD) exams were performed at entry and exit, with a central blinded review. A novel MRA vasculopathy grading scale demonstrated frequent severe baseline left/right vessel stenosis (53%/41% ≥Grade 4); 31% had no vessel stenosis on either side. Baseline parenchymal injury was prevalent (85%/79% subcortical, 53%/37% cortical, 50%/35% subcortical and cortical). Most children had low or uninterpretable baseline middle cerebral artery TCD velocities, which were associated with worse stenoses (incidence risk ratio [IRR] = 5.1, P ≤ .0001 and IRR = 4.1, P < .0001) than normal velocities; only 2% to 12% had any conditional/abnormal velocity. Patients with adjudicated stroke (7) and transient ischemic attacks (19 in 11 standard/8 alternative arm subjects) had substantial parenchymal injury/vessel stenosis. At exit, 1 child (alternative arm) had a new silent infarct, and another had worse stenosis. SWiTCH neuroimaging data document severe parenchymal and vascular abnormalities in children with SCA and stroke and support concerns about chronic transfusions lacking effectiveness for preventing progressive cerebrovascular injury. The novel SWiTCH vasculopathy grading scale warrants validation testing and consideration for use in future clinical trials. This trial was registered at www.clinicaltrials.gov as #NCT00122980.

Effect of chronic transfusion therapy on progression of neurovascular pathology in pediatric patients with sickle cell anemia.

BACKGROUND: Chronic blood transfusion (CBT) is currently the standard of care for primary and secondary stroke prevention in children with sickle cell anemia (SCA). However, the effect of CBT on cerebrovascular pathology is not well known. METHODS: We reviewed children with SCA receiving CBT for abnormal transcranial Doppler (TCD) [n=12] or cerebrovascular accident (CVA) [n=22]. Baseline cerebral magnetic resonance imaging (MRI) and magnetic resonance angiogram (MRA) were compared with the most recent scans available for each patient and independently scored by a neuroradiologist. RESULTS: Thirty-four patients with a mean age of 6.5years at the time of baseline MRI/MRA were studied. Average elapsed time from baseline to most recent scans was 7.3years. Overall, patients experienced worsening vasculopathy, as measured by mean increases in their baseline MRI and MRA scores of +0.76 and +1.03. There was a significant difference in the mean change of MRI/MRA scores between patients who had CVA and abnormal TCD (MRI; +1.23 vs. -0.08, p=0.001 and MRA; +1.54 vs. +0.08, p=0.02). Patients with abnormal baseline MRA had worsening scores compared to those with normal baseline MRA (54% vs. 9.5%, p=0.01). Also, patients who had CVA were more likely to have an abnormal baseline MRA and worsening scores compared to abnormal TCD patients. CONCLUSION: We show that children with CVA experience progression of cerebral vasculopathy despite CBT. In contrast, CBT for abnormal TCD confers protection against the development and/or progression of cerebral vasculopathy. This effect appears to be real given our large cohort of patients with longer follow up as compared to previous studies.

Safety and efficacy of high dose intravenous desferrioxamine for reduction of iron overload in sickle cell disease.

BACKGROUND: Patients with sickle cell disease (SCD) receiving chronic blood transfusions are at risk of developing iron overload and organ toxicity. Chelation therapy with either subcutaneous (SQ) desferrioxamine (DFO) or oral deferasirox is effective in preventing and reducing iron overload but poses significant challenges with patient compliance. Intravenous (IV) infusions of high dose DFO have been utilized in non-compliant patients with heavy iron overload in small case series. PROCEDURE: We review our experience of high dose IV DFO in 27 patients with SCD who had significant iron overload and were noncompliant with subcutaneous (SQ) DFO. All patients were treated in-hospital with DFO 15 mg/kg/hr IV for 48 hr every 2-4 weeks with a mean duration of 19.6 months. RESULTS: We observed a significant decrease in liver iron burden with high dose intermittent IV DFO. Histological examination of liver biopsies revealed a decrease in the grade of liver iron storage. Also there was significant improvement in liver enzymes (ALT, AST) after high dose IV DFO. No audiologic or ophthalmologic toxicity or acute or chronic pulmonary complications were observed. CONCLUSIONS: In our cohort of patients with SCD we observed a significant decrease in liver iron burden with high dose IV DFO. Our patients tolerated the therapy well without any major toxicity. This regimen is safe and may be an option for poorly compliant patients with significant iron overload.

Prevalence and clinical correlates of microalbuminuria in children with sickle cell disease.

Sickle cell disease (SCD) is associated with a large spectrum of renal abnormalities, one of which, microalbuminuria/proteinuria (MA/P), is a known predictor of end-stage renal disease. We studied 90 children with SCD (57% male; mean age 11.4 +/- 5.2 years) to determine the prevalence and examine clinical correlates of MA/P. The average of two spot urine microalbumin-to-creatinine samples obtained 6 months apart was recorded. Medical records were reviewed for demographic and biochemical data. Medication use, resting office blood pressures (BP), vaso-occlusive pain crises (VOC), and monthly transfusions were recorded. Fourteen children (15.5%) had MA/P. Hemoglobin (Hb) levels were significantly lower in the children with MA than in those without MA/P (8.8 +/- 1.1 vs. 9.8 +/- 1.4 g/dL, respectively) and were significantly correlated with MA (rho = 0.24, p = 0.03). Children with MA were more likely to have abnormal BP (p = 0.058), with 5/14 being hypertensive or pre-hypertensive. In a multivariate logistic regression model of MA, both Hb and BP classification remained in the final model. MA is a simple screening biomarker of early kidney injury in children with SCD. Larger studies to evaluate predictive factors of MA and the relationship to BP are needed.

Clinical events after surgical splenectomy in children with sickle cell anemia.

PURPOSE: Despite advances in immune prophylaxis, sepsis remains the most feared complication following splenectomy for acute splenic sequestration crisis (ASSC) in children with sickle cell anemia (SCA). We seek to investigate the true prevalence of sepsis and other complications of splenectomy in this patient population. METHODS: We reviewed the records of children with SCA (HbSS) who underwent splenectomy for ASSC between 1993 and 2008 at a single institution. RESULTS: Fifty-eight patients (33 males) at a median age of 2 years at splenectomy were included with an average post-splenectomy follow-up of 6.4 years (range 6 months-14 years). Thirty-seven patients (64%) underwent laparoscopic splenectomy, and acute chest syndrome (ACS) was the most common post-operative complication (6.9%). There was no difference in the incidence of sepsis pre- and post-splenectomy. The occurrence of vaso-occlusive pain crises (VOC) and ACS was significantly higher after splenectomy. In addition, 14 patients (24%) developed stroke (n = 5) or an abnormal transcranial Doppler (TCD) (n = 9) after splenectomy. CONCLUSION: Our data suggest that splenectomy can be safely performed in children with SCA given a low risk of sepsis. However, the increased incidence of VOC, ACS, and stroke or abnormal TCDs after splenectomy remains a concern.

An unusual ultrasound appearance of renal hemosiderosis in acute sickle cell nephropathy.

Sickle cell disease is the most common inherited blood disorder in the United States. The primary driver of pathology is microvascular occlusion which affects multiple organ systems including the kidney. The renal pathology usually manifests as hematuria, proteinuria, or microalbuminuria, and up to 10% of individuals with homozygous sickle cell disease (HbSS) develop renal failure over their lifetime. At ultrasound, the most common finding is increased size with mild variation in echogenicity of the renal parenchyma. We report the ultrasound appearance of a case of acute sickle cell nephropathy with markedly abnormal, enlarged, and echogenic kidneys due to intravascular hemolysis and hemosiderosis, confirmed by biopsy. Knowledge of this potential presentation of sickle cell nephropathy may help aid in earlier diagnosis of renal complications and avoidance of unnecessary renal biopsies.

Liver biopsy results in patients with sickle cell disease on chronic transfusions: poor correlation with ferritin levels.

BACKGROUND: Chronic transfusions are effective in preventing stroke and other complications of sickle cell disease. The aim of this study was to determine whether serum ferritin levels correlated with liver iron content in sickle cell patients on chronic transfusion. PROCEDURE: Forty-four liver biopsy specimens from 38 patients with homozygous sickle cell anemia (HbSS) and one patient with sickle thalassemia receiving chronic transfusions were studied. Five patients underwent a second liver biopsy for follow up. Three ferritin measurements were used to calculate a mean for each patient. The association between serum ferritin levels and liver iron quantitation was measured using the Spearman rank correlation, and sensitivity and specificity were determined for selected threshold values of serum ferritin. RESULTS: Serum ferritin levels ranged from 515 to 6076 ng/ml, liver iron concentration ranged from 1.8 to 67.97 mg/g dry weight. The amount of iron per gram liver dry weight was moderately correlated with serum ferritin values (r = 0.46). The correlation of duration of transfusion with serum ferritin (r = 0.40) and with liver iron content (r = 0.41) also indicated moderate correlation. Liver biopsy results led to changes in the management after 29/44 (66%) of the biopsies. Serum ferritin >/=2500 ng/ml predicted high liver iron content (>/=7 mg/g), with a sensitivity of 62.5% and a specificity of 77.8%. CONCLUSION: We found a poor correlation between serum ferritin levels and liver iron content (LIC). Despite being on chelation therapy, many patients on chronic transfusion had high levels of liver iron. Measurement of LIC is highly recommended in these patients.

Radiographic predictors of neurocognitive functioning in pediatric Sickle Cell disease.

We compared magnetic resonance imaging (MRI), magnetic resonance angiography, and transcranial Doppler ultrasonography as predictors of specific neurocognitive functions in children with sickle cell disease. Participants were 27 children with sickle cell anemia (hemoglobin SS) who were participants in the Stroke Prevention Trial in Sickle Cell Anemia (STOP) and had no documented history of stroke. Children's MRIs were classified as normal or silent infarct, and their magnetic resonance angiograms were classified as normal or abnormal. The highest time-averaged mean flow velocity on transcranial Doppler ultrasonographic examination of the major cerebral arteries was analyzed. Age and hematocrit also were analyzed as predictor variables. The battery of neurocognitive tests included measures of intellectual functioning, academic achievement, attention, memory, visual-motor integration, and executive functions. MRI, magnetic resonance angiography, transcranial Doppler ultrasonography, age, and hematocrit were analyzed as predictors of participants' performance on the various measures of neurocognitive functioning. Age and hematocrit were robust predictors of a number of global and specific neurocognitive functions. When age and hematocrit were controlled, transcranial Doppler ultrasonography was a significantly unique predictor of verbal memory. We found an association between low hemoglobin and neurocognitive impairment. We also found that abnormalities on transcranial Doppler ultrasonography can herald subtle neurocognitive deficits. (J Child Neurol 2006;21:37-44).

Ameliorating attention problems in children with sickle cell disease: a pilot study of methylphenidate.

OBJECTIVE: This pilot study examined whether methylphenidate (MPH) was effective in enhancing cognitive performance and attention for children with sickle cell disease (SCD) with cerebrovascular complications who evidence attention problems. METHODS: In this multisite, pilot study, we evaluated 2 separate double-blind controlled clinical trials, including a laboratory trial of the short-term efficacy of MPH, with the second study a 3-week home/school crossover trial evaluating the efficacy of MPH. The laboratory trial included 14 participants between the age of 7 and 16 years. Assessments included measures of sustained attention, reaction time, executive functions, and verbal memory. The home/school trial included 20 participants. The outcome measures were parent and teacher ratings of attention. The first study compared MPH with placebo, while the second trial compared placebo, low-dose (LD) MPH, and moderate-dose MPH. RESULTS: In the laboratory trial, significant effects were revealed for measures of memory and inhibitory control. Parent and teacher reports from the home/school trial indicate that moderate-dose MPH produced superior improvement in attention relative to the placebo and LD MPH. CONCLUSIONS: Stimulant medication positively impacted select measures of memory and inhibitory control in some children with SCD. Attention, as rated by parent and teachers, was improved for a greater number of children and adolescents on higher doses of MPH relative to LD MPH and placebo. Stimulant medication may provide an effective intervention for some children with SCD and cerebrovascular complications who demonstrate attention problems.

Outcome of splenectomy in children younger than 4 years with sickle cell disease.

PURPOSE: Removal of the spleen in patients younger than 4 years has been reported to carry an increased risk of postsplenectomy sepsis and has not been universally accepted. We reviewed our experience with splenectomy in children with acute splenic sequestration crisis (ASSC) younger than 4 years. METHODS: The study involved retrospective review of demographic and operative data, number of ASSC, operative complications, infections, and death. RESULTS: From 1993 to 2008, 53 patients (28 males, 25 females) younger than 4 years had open (43.8%) or laparoscopic (56.6%) splenectomy after one or more events of ASSC. Six (11.3%) were younger than 18 months, 28 (52.8%) were 18 to 24 months old, and 21 (39.6%) were 24 to 48 months old. Operative complications were diaphragm laceration (laparoscopy, n = 3; 5.7%) and reoperation for bleeding (open, n = 1; 1.8%). Length of stay was similar for laparoscopic (3.6 days) vs open (3.8 days) splenectomy. Mean postoperative follow-up was 5.6 years. In 353 postsplenectomy admissions, 3 (5.7%) patients had positive blood cultures requiring treatment. Three (5.7%) patients died within the 15-year study period; one (1.8%) had documented pneumococcal sepsis. DISCUSSION: The advantage of early splenectomy may outweigh the risks of long-term transfusion. Splenectomy in young children with sickle cell disease carries a low risk of postsplenectomy sepsis with appropriate vaccination and prophylactic antibiotics. We conclude that splenectomy in young children with ASSC is safe and effective, especially with penicillin prophylaxis and improved vaccination strategies.

Transcranial Doppler ultrasonography and neurocognitive functioning in children with sickle cell disease.

OBJECTIVE: We examined the relationship between cerebral blood flow velocity, measured by transcranial Doppler (TCD) ultrasonography, and neurocognitive functioning. METHODS: Participants were 60 children who had sickle cell disease (HbSS) and had no documented history of stroke. Children were classified according to Stroke Prevention Trial in Sickle Cell Anemia criteria (normal, conditional, and abnormal), and their performance was compared on measures of intellectual abilities, academic achievement, sustained attention/concentration, executive function, and parent and teacher ratings of executive function. RESULTS: Children with abnormal TCD values performed more poorly than children with conditional TCD values on measures of verbal intelligence and executive function. Children with conditional TCD values performed more poorly than children with normal TCD values on measures of sustained attention/concentration and executive function. TCD values also were a significant predictor of auditory working memory in exploratory analyses. CONCLUSIONS: Our findings support the hypothesis that neurocognitive functions subserved by the frontal systems (eg, sustained attention/concentration and executive function) seem to be the most useful indices of progressive cerebrovasculopathy in children with HbSS disease.