Update in Hospital Medicine

1
Update in Hospital Medicine

• Nicole Artz, MD
• David Lovinger, MD
• Nilam Soni, MD
• Program in Hospital Medicine
• University of Chicago

2
Healthcare-Associated Pneumonia Requiring
Hospital Admission

• Carratala J, Arch Intern Med/Vol 167, July 2007

3
Objective

• Discern the epidemiology, causative organisms,
  antibiotic susceptibilities, and outcomes of HCAP
  requiring hospitalization

4
Background

• Proposed as new category of resp infection in
  2005 ATS/IDSA guidelines
• Pneumonia occuring in a pt w/ extensive
  healthcare contact
• Home infusion therapy or wound therapy
• Resident of NH or long-term care facility
• Hospitalization within prior 90 days
• Chronic dialysis within prior 30 days
• Family member with multidrug resistant pathogen
• Limited data to validate entity or guide therapy

ATS/IDSA guidelines for mgt of adults with HAP,
VAP, HCAP, Amer J Respir Crit Care Med. 2005
5
Methods

• Prospective observational study (1/2001-12/2004)
• 900 bed university hospital in Spain
• Hospitalized adults with pneumonia (excluded
  severely immunosuppressed patients)
• Classified as CAP vs HCAP using standard protocol

6
Methods Cont

• Evaluation for infecting organism
• 2 sets blood cultures
• Sputum gram stain and culture
• Acute and convalescent serologic studies
• Urinary antigen for S. pneumo and L. pneumophila
  performed at discretion of attending
• Antibiotic therapy initiated in the ED according
  to hospital guidelines
• Ceftriaxone or Augmentin /- macrolide OR
  Levofloxacin

7
Methods Cont

• Pts followed daily by investigators clinical
  data tracked and recorded
• Etiologic diagnosis
• Definitive
• Pathogen in usually sterile specimen
• L pneumophila in sputum
• L pneumophila or S. pneumo antigen in urine
• 4-fold ? in antibody titer,
• Seroconversion for atypical pathogens
• Presumptive
• Predominant microorganism isolated from purulent
  sputum sample w/ compatible gram stain
• Aspiration pneumonia (pts w/ risk factors and
  involvement of dependent pulm segment or
  necrotizing pneumonia)

8
Results- Patient Characteristics

• 727 adults hospitalized with pneumonia

9
Results- Etiology
10
Results- Clinical Outcomes
P.007
P.03
11
Limitations

• Single institution study
• Different country (Spain)
• Number of patients with HCAP small
• Cant draw conclusions about cause of higher
  mortality

12
Implications

• HCAP should be regarded as separate category
• May need to target initial therapy differently
• Larger studies needed from different
  hospitals/geographical areas to further define
  etiology, clinical outcomes, appropriate initial
  treatment strategies

13
Randomized Study of Basal-Bolus Insulin Therapy
in the Inpatient Management of Patients with Type
2 Diabetes (RABBIT 2 TRIAL)

• Umpierrez G, Diabetes Care, Vol 30 (9) September
  2007

14
Objective

• Study the optimal management of hyperglycemia in
  non-intensive care unit patients with type 2
  diabetes

15
Background

• Strong observational data linking hyperglycemia
  with adverse outcomes among hospitalized patients
  (ICU and non-ICU)
• Prospective randomized trials in critically ill
  pts and pts w/ AMI show reduced morbidity and
  mortality w/ intensive control of hyperglycemia
• Limited data evaluating interventions/outcomes in
  non critically ill patients

Umpierrez, GE, J Clin Endocrinol Metab, 2002
Clement S, Diabetes Care, 2004 Krinsley, JS,
Mayo Clin Proc, 2003 Van den Berghe, N Engl J
Med 2001 and 2006
16
Methods

• Multicenter, open-label, randomized study

• Inclusion Criteria
• General medical pts
• Insulin-naive
• Known h/o DM
• Ages 18-80 yrs
• BG 140-400 mg/dl
• Absence of DKA

• Exclusion Criteria
• No known h/o DM
• ICU admission
• Corticosteroid use
• Expected surgery
• Liver disease
• Creatinine gt/ 3mg/dl
• Pregnancy
• Mental condition precluding informed consent

17
Methods Cont

• Pts managed by internal medicine residents with
  assigned protocol
• Endocrinologist rounded daily with team
• Randomized to basal/bolus regimen (glargine and
  glulisine) vs SSI
• Oral agents discontinued at admission

18
Basal/Bolus Insulin
Breakfast
Lunch
Dinner
Lispro Lispro Lispro
Plasma insulin
Glargine
400
1600
2000
2400
400
800
1200
800
Time
19
Methods Cont..

• Basal-Bolus Regimen
• 0.4 units/kg for admission BG 140-200 mg/dl
• 0.5 units/kg for admit BG 201-400 mg/dl
• 50 basal, 50 prandial (bolus)
• Correction factor/supplemental glulisine for BS
  gt140
• 20 increase in glargine dose for fasting or mean
  BG gt140
• 20 decrease in glargine for BG lt70 mg/dl

20
Methods

• SSI Group
• Regular insulin 4Xs daily for BG gt 140 mg/dl
• 3 different SSI protocols (sensitive, usual,
  resistant)
• Pts eating received usual SSI protocol
• NPO pts received insulin sensitive SSI protocol
• Adjusted up or down daily based on BG
• If mean daily BG was gt240 or 3 consecutive values
  gt 240 on maximal SSI regimen, pts switched to a
  basal-bolus regimen (14).

21
Results
Figure 1 Changes in blood glucose concentrations
in patients treated with glargine plus glulisine
(?) and with SSI (o). P lt 0.01 P lt 0.05.
22
Results
23
Results

• Figure 2 Mean blood glucose concentration in
  subjects who remained with severe hyperglycemia
  despite increasing doses of regular insulin per
  the sliding-scale protocol (o). Glycemic control
  rapidly improved after switching to the
  basal-bolus insulin regimen (). P lt 0.05.

24
Limitations

• Did not include patients with new onset
  hyperglycemia
• Excluded patients with renal insufficiency,
  already on insulin, or on steroids
• Not powered to determine differences in mortality
  or other clinical outcomes
• Endocrinologist rounded with medicine teams daily

25
Implications

• Basal-Bolus insulin regimens can be effective and
  safe in non-critically ill patients when used
  correctly
• Need trials examining clinically important
  outcomes (short and long-term)

26
Renal Protection for Coronary Angiography in
Advanced Renal Failure Patients by Prophylactic
Hemodialysis

• Lee, PT, Chou KJ, et al. Journal of the American
  College of Cardiology, 2007501015-20.

27
Objective

• Evaluate the effectiveness of prophylactic
  hemodialysis in patients who are the highest risk
  for Contrast-Induced Nephropathy (CIN)

28
Background

• CIN is the 3rd most common cause of ARF in
  hospitalized patients.
• Development of CIN is associated with an
  increased risk of
• Prolonged hospitalization
• Permanent worsening of renal function
• Need for HD
• Death
• Optimal prevention strategies are unclear.

29
Background, Contd

• There many studies on CIN prevention, and
  effective strategies include
• Hydration with saline
• Minimizing contrast bolus
• N-Acetylcysteine
• HCO3-
• Comparisons between studies are difficult
  because
• Different defns of ARF (25 decr GFR, 1 mg/dL
  incr SCr)
• Different baseline SCR (gt1.5 to 5)
• Different populations
• Different procedures and dye loads (cath, CT)

30
Methods

• 82 consecutive pts with advanced renal failure
  referred for coronary angiography.
• SCr avg 4.9 mg/dl and stable x 1 mo (entry
  criteria gt 3.5 mg/dl)
• Most pts w/CAD, DM, and HTN
• Avg EF 45
• No recent nephrotoxins or dye load (7d)
• No NAC, mannitol, dopamine, theophylline

31
Methods, contd

• Pts were randomized to either prophylactic HD or
  nothing, and both groups were given a 1 mL/kg/hr
  infusion of NS x 18h.
• No ultrafiltration was performed.
• Primary endpoint was change in GFR calculated by
  24-hour urine collected before procedure and on
  day 4.
• Secondary endpoints were temporary or permanent
  need for HD in either group.

32
Results Primary Endpoint

• Day 4 CrCl was reduced relative to baseline in
  the control group, but not in HD group (p0.008).
• No adverse events from line placement.

33
Primary outcome Change in GFR on Day 1 and Day 4
p-value for the difference in Day 4 clearance
0.008
34
Results Secondary Endpoints

• Peak SCr and SCr at discharge were significantly
  higher in the control group than in the HD group
  (plt0.001 for both.)
• More patients in the control group had
  significant, long-term renal injury or needed
  temporary or permanent HD than in the HD group.
• LOS was 2x longer in the control group.

35
Secondary Outcomes
P-values for each group respectively lt0.001,
0.018, 0.017 and lt0.001
36
Limitations

• Unblinded
• Very advanced renal failure (small subset).
• Prior negative trials
• No effect at lower levels of SCr
• Ultrafiltration likely harmful as volume
  depletion is a significant risk factor for CIN
• Need cooperating nephrologist and patient.

37
Implications

• Potentially significant way to treat patients
  with advanced renal failure who need procedure
  involving IV contrast.
• A big benefit for patients at the highest risk.

38
Length of Hospital Stay and Postdischage
Mortality in Patients with Pulmonary Embolism

• Aujesky D, Stone RA, Kim S, Crick EJ, Fine MJ.
  Archives of Internal Medicine. 2008 168(7),
  706-712.

39
Objective

• Determine the effect of length of stay (LOS) on
  mortality in patients hospitalized with a
  pulmonary embolism.

40
LOS and Mortality in Patients with Pulmonary
Embolism

• PE is a serious medical condition, with
  substantial morbidity and mortality.
• Optimal length of stay unclear in era when all
  LOS is decreasing.
• How do outcomes interact with LOS?
• How does LOS interact with PE severity?

41
Methods

• Retrospective cohort study
• 15,531 patients
• Administrative and clinical data
• Inclusion criteria
• Primary dx PE, or
• Secondary dx PE and primary dx c/w PE (SOB,
  resp failure, syncope, cardiac arrest, etc)
• Patients with only a secondary dx of PE or
  transferred from another facility were excluded
• Community acquired PE

42
Pulmonary Embolism Severity Index (PESI)

• Used a previously determined risk stratification
  score for PE
• Risk stratification into 5 groups based on score
• Class I lt 65
• Class II 66-85
• Class III 86-105
• Class IV 106-125
• Class V gt 126
• Patterned on the PORT score
• Overall mortality by class
• Class I 1.1
• Class II 3.1
• Class III 6.5
• Class IV 10.4
• Class V 24.5

• Age in years
• Male gender (10)
• Cancer (30)
• CHF (10)
• Lung dz (10)
• Pulse gt 110 (20)
• SBP lt 100 (30)
• Resp gt 30 (20)
• Altered mental status (60)
• SaO2 lt 90 (20)

43
Mortality and PESI Score1
1Aujesky D, Obrosky S, Stone RA, Auble TE, Arnaud
P, Cornuz, Roy P, Fine MJ. Derivation and
Validation of a Prognostic Model for Pulmonary
Embolism. Am J Respir Crit Care Med. 2005 172,
1041-1046.
44
Short LOS in PE is associated with Increased
Mortality

• Patients were stratified by LOS in quartiles and
  by PE severity (PESI)
• Q1 lt 4d, Q2 5-6d, Q3 7-8d, Q4 gt 8d
• Discharge in Q1 has an excess risk of death at 30
  days (RR 1.55)
• Discharge in Q4 also has an excess risk (RR
  2.39)
• Uninsured patients had longer LOS and better
  outcomes after discharge
• Not a causal link, but implied mechanism
• Unrecognized clinical instability at discharge
• Insufficiently stable anticoagulation

45
Mortality and LOS
plt0.001 for comparison between quartiles 1 and 2
LOS Quartile Q1 lt 4d Q2 5-6d Q3 7-8d Q4 gt
8d
46
PESI Score and LOS Quartile
47
Implications

• PE remains a morbid and mortal condition.
• Comorbid disease increases risk death at 30 days
  significantly.
• PESI is a simple scoring tool for identifying
  high risk patients.
• Ensuring a therapeutic INR and close follow-up is
  prudent.

48
Limitations

• Not a prospective, randomized trial.
• Cannot attribute causation for mortality.

49
Zoledronic Acid and Clinical Fractures and
Mortality after Hip Fracture

• Lyles KW, Colon-Emeric CS, Magaziner JS, et al.
• New England Journal of Medicine 20073571799-809

50
Objective

• Determine the safety and efficacy of zoledronic
  acid administration for prevention of new
  clinical fractures in patients who have had
  recent hip fracture surgery

51
Background

• Mortality 15-25 in first year after hip fracture
• New osteoporotic fractures occur 10.4 per 100
  patients/year after hip fracture
• Few patients receive bisphosphonates after hip
  fracture
• Zoledronic acid is a bisphosphonate given
  intravenously once yearly
• Zoledronic acid has been shown to reduce hip,
  vertebral, and nonvertebral fractures in
  postmenopausal osteoporosis

52
Methods

• International, multicenter, randomized,
  double-blind, placebo-controlled study
• Zoledronic acid or placebo infusion within 90
  days of hip fracture and every 1 year thereafter
• All patients received calcium (1000-1500 mg) and
  vitamin D (800-1200 IU) daily
• If 25-hydroxyvitamin D lt15 ng/ml or not known,
  loading dose of vitamin D2 or D3 given orally or
  IM (50,000-125,000 IU) 14 days prior to infusion

53
Methods

• Follow up with quarterly phone calls and annual
  clinic visits
• Monitored for up to 5 yrs
• Study stopped early after 185 events accrued in
  placebo group
• Concomitant use of nasal calcitonin, SERM, HRT,
  tibolone, and external hip protectors allowed at
  discretion of investigator
• Exclusions CrCl lt30 ml/min, Ca gt11 or lt8, active
  cancer, life expectancy lt6 mo

54
Methods

• Outcomes
• Primary New clinical fractures
• Secondary
• Change BMD in non-fractured hip
• New vertebral, nonvertebral, and hip fractures
• Death

55
Methods

• Definitions for New Fractures
• Vertebral fractures back pain reduction in
  vertebral body height (blinded review of
  difficult cases)
• Nonvertebral fractures positive radiograph,
  report, or medical record documentation
• Delayed union of hip fracture persistent pain
  or inability to bear weight radiographic
  evidence

56
Results

• 2127 patients ? 1065 zoledronic acid,
• 1062 placebo
• Median follow-up 1.9 years
• Similar baseline characteristics
• Average age 74
• 90 were white
• 75 were female
• 41 had T score lt -2.5 at femoral neck

57
Results
58
Results
59
Results

• Adverse events similar in both groups
• Zoledronic acid group reported greater
• Pyrexia (8.7 vs. 3.1)
• Myalgia (4.9 vs. 2.7)
• Bone pain (3.2 vs. 1.0)
• Musculoskeletal pain (3.1 vs. 1.2)
• No difference in cardiovascular events
• No reported cases of osteonecrosis of jaw

60
Limitations

• Effects of previous use of bisphosphonates and
  parathyroid hormone permitted after a washout
  period
• Limited ethnic diversity (gt90 were white and 1
  were black)
• Incidence of delayed union of hip gt in zoledronic
  acid group, but not statistically significant
• No comparison to standard therapy (oral
  bisphosphonate, calcium vitamin D)

61
Implications

• Annual infusion of zoledronic acid after hip
  fracture surgery reduces new fractures and
  improves survival
• Option for patients who are unable or unwilling
  to take an oral bisphosphonate
• Should be given with oral calcium and
• vitamin D

62
Recombinant Factor VIIa for the Prevention and
Treatment of Bleeding in Patients Without
Haemophilia

• Stanworth SJ, Birchall J, Doree CJ, Hyde C,
• Cochrane Database of Systematic Reviews,
• April 2007

63
Objective

• Assess the effectiveness of recombinant factor
  VIIa when used prophylactically to prevent
  bleeding, and when used therapeutically to
  control active bleeding in patient without
  hemophilia

64
Background

• Recombinant FVIIa is licensed for use only in
  patients with hemophilia
• Increasing use for off-label indications to
  prevent and/or stop bleeding
• Potential to reduce need for transfusion of blood
  products
• High Cost 1.2 mg 1,328 (per vial)
• 2.4 mg.... 2,658
• 4.8 mg. 5,318

65
Methods

• Systematic Review by Cochrane Collaboration
• Data Sources Major national and international
  electronic medical databases (to March 2006)
• Inclusion Criteria for this Review
• Randomized controlled trials
• Pts at risk for blood loss or treated for
  bleeding
• Pts with hemostatic defects, such as hemophilia,
  excluded
• Outcomes Mortality, bleeding, number of
  transfusions, number of patients transfused, and
  thromboembolic events

66
Methods

• Methods of Review
• 2 authors screened papers
• Methodological Quality
• Generation of random sequence
• Concealment of treatment allocation
• Blinding of clinicians, participants, and outcome
  assessors
• Proportion of participants included in main
  analysis
• Equal use of co-interventions in study arms

67
Methods

• Description of Studies
• 13 randomized controlled studies identified
• Prophylactic Trials
• 6 trials included
• Participants varied
• (traumatic pelvic fractures, radical
  prostatectomy, partial hepatectomy, liver
  transplantation, cardiac surgery)
• All 6 trials compared rFVIIa vs. placebo
• Significant differences in dosing and
  administration
• (40 mcg/kg to 360 mcg/kg)
• All trials had threats to validity
• (randomization, allocation concealment,
  patient disposition)

68
Methods

• Descriptions of Studies (contd)
• Therapeutic Trials
• 7 trials included
• Participants varied
• (post-stem cell transplant, hemorrhagic Dengue
  fever, severe trauma, cirrhotics with GI
  bleeding, intracerebral hemorrhage)
• All trials placebo controlled
• Significant differences in dosing and
  administration
• (40 mcg/kg to 1120 mcg/kg)
• Only 1 trial without threats to validity

69
Results Prophylactic Trials

• No statistically significant differences in
  death, blood loss, blood transfusions, number of
  patients transfused, or thromboembolic events
  from pooled data
• Only 1 small study reported statistically
  significant differences in blood loss,
  transfusion requirements, and number of patients
  transfused

70
Results Prophylactic Trials - Death
71
Results Prophylactic Trials - Blood Loss
72
Results Prophylactic Trials - Transfusion
Requirements
73
Results Prophylactic Trials - Patients Transfused
74
Results Prophylactic Trials - Thromboembolic
Events
75
Results Therapeutic Trials

• Death
• No significant reduction in pooled data
• 1 study reported reduction
• Reduction in Bleeding
• No significant reduction in pooled data
• 1 study qualitatively showed reduction in volume
  of ICH and reduction in disability
• Transfusion Requirements, Number of Patients
  Transfused, and Thromboembolic Events
• No significant difference in pooled data

76
Results Therapeutic Trials - Death
77
ResultsTherapeutic Trials Reduction in Bleeding
78
Results Therapeutic Trials - Transfusion
Requirements
79
ResultsTherapeutic Trials - Number of Patients
Transfused
80
ResultsTherapeutic Trials - Thromboembolic Events
81
Results Subgroup Analysis

• Adverse Events
• No significant difference in thromboembolic
  events in combined analysis of both prophylactic
  and therapeutic trials
• Low vs. High Dose rFVIIa
• No significant difference based on dose
• Nonsignificant trend toward greater effect at
  higher dose

82
Limitations

• Wide range of patient populations (cardiac
  surgery, hemorrhagic Dengue fever, trauma, etc.)
• Dosing schedules varied greatly (clarify optimal
  dosage and dosing interval)
• Effects of thrombocytopenia and platelet
  dysfunction not included
• 1 study showing benefit in ICH could not be
  incorporated into analysis

83
Limitations

• Underestimation of thromboembolic events
• All RCTs excluded pts with history of thrombosis
  or vaso-occlusive disease
• Clinical practice settings suspected to have
  higher risk of thrombosis
• FDA issued warning against off-label uses based
  on many reports of thrombosis, especially CVAs

84
Implications

• Administration of recombinant factor VII for
  prophylaxis or treatment of bleeding in patients
  without hemophilia is not supported by current
  randomized, controlled trials
• Use should be restricted to licensed indications
  until more data available
• Several ongoing trials