NSF - how real?

Motivation: A few months ago, I was lounging in the neurology office when someone called to ask about the possibility of brain MRI with contrast in a patient with kidney disease.  The resident answered, "Of course, not!"  After all, gadolinium based agents have been implicated in nephrogenic systemic fibrosis (NSF).  When the resident placed the phone on the cradle, a fellow in the room smirked and remarked that our fear of NSF is overblown.  He explained that cases of NSF occur rarely and that fear of litigation probably drove our prohibition.  Well, just how common is nephrogenic systemic fibrosis after gadolinium contrast exposure?

For background, nephrogenic systemic fibrosis was first described in 2000 and is clinically characterized by thickening and hardening of skin with "brawny" hyperpigmentation especially of the extremities.  Patients experience neuropathic pain in affected areas and suffer from flexion contractures and pressure ulcers.

Paper: Association of Gadolinium Based Magnetic Resonance Imaging Contrast Agents and Nephrogenic Systemic Fibrosis.  Bhave, G. et. al. The Journal of Urology (2008) 180: 830-835. http://www.jurology.com/article/S0022-5347(08)01225-1/abstract

Results: 
Number of known cases: The largest case registry for NSF (Yale NSF case registry) contains about 200 cases. Adding all other reported cases, at the end of 2006, there were at most 400-500 cases of NSF worldwide.

Relation to Kidney Disease: No case of NSF has been described for GFR greater than 30 mL/min.  Cases which seemingly involved patients with GFR > 30 mL/min are likely due to calculation error since in acute kidney failure, serum creatinine levels do not instantaneously reach steady state and give rise to errors in GFR estimation.

Link with Gadolinium Exposure: More than 95% of known cases of NSF have had gadolinium exposure in the weeks to months prior to presentation.  A very small minority of putative NSF cases have not had gadolinium exposure.  The upper limits of lag times from gadolinium exposure to NSF are about 1-2 years.

Incidence after Gadolinium Exposure: In single center cohorts, the proportion of patients with kidney failure developing NSF after gadolinium exposure is about 2-5%.  The authors challenge this assumption based on a simple calculation.  Before 2000, there were no restrictions on gadolinium administration.  In the ten prior years, there were 50 million MRI contrast studies, and given the 0.1% prevalence of end stage renal disesaes (ESRD) in the U.S., there have been conservatively about 50,000 MRI contrast studies performed in patients on ESRD.  Given that there are at most 500 known cases of NSF, the incidence is likely no more than 1% after gadolinium exposure in patients in ESRD.


Discussion: In summary, NSF is a rare but real danger.  What I thought was an especially valuable point to keep in mind is that in cases of acute kidney failure, the serum creatinine level is an imperfect measure, and the working assumption ought to be perhaps that gadolinium is contraindicated despite seemingly permissive creatinine levels.  On the flip side, radiologists are hesitant to administer gadolinium in patients with GFR<60 mL/min but greater than 30 mL/min.  There have been no reported cases of NSF in this group, and this cautious approach may be excessive and needs to be reevaluated. 


Finally, is there any way to prevent NSF? From a pathophysiology viewpoint, gadolinium ion is toxic to human beings, and contrast agents consist of gadolinium chelated to other molecules to facilitate excretion and limit exposure of tissue to gadolinium ions.  In renal failure, with prolonged exposure, gadolinium is lost from chelation and produces toxic effects.  In the future, the thought is that with stronger chelating molecules, we may be able to further limit gadolinium loss from chelation and prevent toxic effects before excretion through dialysis or urination.

New Weapon in the Fight Against C.Diff

Introduction

Throughout my medical school career, there are many things, both good and bad which I will never forget, among them is the pungent odor of a C.difficile infection. Its an unmistakable stink which brings back memories of awkwardly trying to write a note or perform a physical exam while wearing one of those big yellow isolation gowns. C. diff's unshakable presence in our hospitals is only expected to get worse as our careless over-use of antibiotics creates more opportunities for c.diff to out compete the normal colonic flora.

Traditionally, C.diff infections have been treated with Flagyl firstline and Vancomycin for those who failed Flagyl or have fulminant disease. However, due to increasing resistance to Flagyl, Vancomycin is rapidly becoming the only effective drug for many patients. However, even Vancomycin sometimes cannot eliminate this nasty critter causing patients to relapse almost as soon as they leave the hospital. The result is chronic, uncontrollable malodorous diarrhea that can destroy a patient's quality of life and create nightmares for hospital infection control and cost billions of dollars for our health care system.

However, hope is on the horizon with a new antibiotic -Fidaxomicin, which has recently completed phase 3 trials. Fidaxomicin is a macrolide antibiotic produced by Optimer Pharma which has shown higher in vitro activity against c.diff than vancomycin. In an article published in February of 2011 in the NEJM, Louie et al. present results from a phase III trial involving 629 patients.

Louie TJ, Miller MA, Mullane KM, Weiss K, Lentnek A, Golan Y, Gorbach S, Sears P, Shue YK; OPT-80-003 Clinical Study Group. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011 Feb 3;364(5):422-31.Methods: Patients were selected whom had diarrhea for 24 hours and either c.diff toxin A or B.

Patients could have received up to 4 doses of Flagyl or Vanc but no other therapy in the 24 hrs before randomization. Patients with fulminant c.diff or >1 recurrence of c.diff in the past 3 month were excluded. Patients were randomized to a 10 day course of either 200mg of Fidaxomicin q12h or 125mg of Vanc q6h. Patients were stratified according to whether this is their first or second episode of c.diff. All patients were followed for at least 28 days following the end of treatment.

Outcomes measured were:

1. clinical cure defined as cessation of diarrhea and no need for additional treatment.

2. Treatment failure was defined as continuation of diarrhea or need for additional therapy.

3. Global cure was defined as no recurrence within the 28 day follow up after end of therapy.

Patients were analyzed as modified intention to treat if they took at least one dose of medication.

Results:

A total of 596 patients were analyzed in the modified intention to treat analysis of which 92% actually adhered to the protocol. They did not differ in baseline characteristics.

Figure 1. mITT=modified intention to treat, PP=per protocol.

As shown in figure 1. Fidaxomicin was as equally efficacious as vancomycin in achieving clinical cure (resolution of diarrhea, no need for additional Rx). However, it achieved a 40% relative reduction in recurrence compared to vancomycin (absolute rate reduction of recurrence from 25% to 15%) (p=0.005).

s shown in Figure 2, in subgroup analysis, Fidaxomicin was superior to or as equally efficacious as Vancomycin at controlling C.diff recurrence in almost every subgroup save for 1. This subgroup comprised of patients with a certain genotype of c.diff known as NAP1/B1/027. For this group, fewer patients had relapse of c.diff after vancomycin treatment (21%) compared to fidaxomicin (27%) however this difference was not statistically significant.

Figure 2.

Safety wise, the rate of adverse and serious adverse reaction was similar in patients treated with Fidaxomicin or Vancomycin.

Discussion:

C.diff is a particularly difficult disease to treat (hence the name) because it is resistant to so many different antibiotics and because even successfully treated patients recur as much as 30% of the time within 60 days. More worryingly, strains of c.diff are becoming resistant to our two current standards of care: Vanc and Flagyl.

Louie et al. show in this study that Fidaxomicin is as efficacious and safe as vancomycin in treating acute infections of c.diff and perhaps more effective at eliminating recurrences. In addition, Fidaxomicin was previously shown to have poor system absorption through the GI tract, a positive attribute because it increases the concentration of the drug which actually reaches the colon after oral administration and also decreases systemic side effects.

The only wrinkle in all of this good news is that the 36% of patients with an aggressive strain of c.diff BI/NAP1/027 do not seem to obtain any additional reduction in recurrence with Fidaxomicin as compared to vanc. This is worrying because patients with this strain of c.diff is the most in need of a better treatment option.

Overall however, fidaxomicin represents an important addition to our current inventory of Flagyl and Vancomycin for the treatment of c.diff.

Diagnosing PE by Blood Gas

Motivation: On an early morning at 5:30 am last winter, I was huddling with my surgery team waiting for our chief to arrive and start rounding.  In the haze of early morning stupor, I heard one of the residents mention that overnight someone was short of breath.  He had called one of his fellow surgical residents, who had advised him to draw a blood gas to rule out pulmonary embolism (PE).  One of the other members of the team was about to say something when the chief arrived, and we cut short our talk to begin marching to the patient rooms.  But, I wondered how sensitive is an ABG with its characteristic signs of hypoxemia and hypocapnia in ruling out PE?

Paper: Diagnostic Value of Arterial Blood Gas Measurement in Suspected Pulmonary Embolism.  Rodger, M., et. al. Am. J. Respir. Crit. Care Med. (2000) 162: 2105-2108.  http://ajrccm.atsjournals.org/cgi/content/full/162/6/2105

Methods: For a 30 month period, consecutive patients (inpatient and outpatient) suspected of PE were subjected to a blood gas and D-dimer test.  Referring clinicians were then asked to provide a clinical gestalt of the likelihood of PE.  Subsequently, all patients underwent V/Q scanning.  For low probability V/Q scan with high clinical probability of PE or high probability V/Q scan with low clinical probability, patients were referred for pulmonary angiogram at the clinician's discretion.  Inclusion criteria for patients were essentially greater than 18 years of age with capacity for informed consent and physiological capability to undergo pulmonary angiogram if necessary.

Results: 
Patient Selection: In total, 246 patients were considered for PE.  In 49 patients, PE was accepted as the final diagnosis and ruled out in 163 other patients.  In 34 patients, the final diagnosis was unclassified.  These patients were not referred for angiogram by their clinicians but had either low probability V/Q scan with high pre-test likelihood or high probability V/Q scan with low pre-test likelihood.  The patients deemed unclassified were removed from further analysis.

Blood Gas Measurements: The clinical variable PaO2<80 mm Hg was present in 57.9% of patients with PE and 46.6% of patients without PE.  The clinical variable PaCO2<36 mm Hg was present in 44.4% of patients with PE and 39.7% of patients without PE.  Other clinical rule results are as follows:

• Abnormal (A-a) gradient- Sensitivity: 84.2%, Specificity: 27.4%, PPV: 27.4%, NPV: 84.2%
• D-dimer positive - Sensitivity: 83.0%, Specificity: 57.6%, PPV: 39%, NPV: 91.2%
• PaO2<80 mm Hg or D-dimer positive - Sensitivity: 91.9%, Specificity: 32.4%, PPV: 32.4%, NPV: 91.9%
• PaO2<80 mm Hg or D-dimer positive or Respiratory Rate>20 breaths/min - Sensitivity: 96.9%, Specificity: 21.3%, PPV: 30.7%, NPV: 95.0%
• PaCO2<36 mm Hg or Abnormal (A-a) O2 gradient - Sensitivity: 91.9%, Specificity: 14.7%, PPV: 25.6%, NPV: 85.0%

Discussion: To rule out PE, we ideally want clinical criteria with high sensitivity.  Individually, hypoxemia and hypocapnia have really poor sensitivities at 57.9% and 44.4%!  Calculating an abnormal alveolar-arterial gradient is a more sensitive indicator for PE, but the negative predictive value (84.2%) is still unacceptably low.  While evaluating the results, I was surprised to see that a D-dimer test was no more sensitive than an abnormal A-a gradient.  The D-dimer has the advantage of specificity rather than sensitivity over the A-a gradient.  If I were stuck on an island without radiology, I would choose the rule of PaO2<80 or D-dimer positive criteria to start ruling out PE though we would miss about 8% of pulmonary embolism cases.  With an estimated untreated mortality of 30%, such an approach would still be dangerous.  This study shows that at present, radiology remains an integral part of ruling out PE.

This study has some limitations.  Of the 246 patients originally included in the study, the diagnosis remained indeterminate in 34 patients.  Often these patients are the most troubling because they have a mismatch in the clinical probability and probability provided by V/Q scan.  A very interesting question is whether blood gas results could be used to further stratify risk status in these patients with intermediate risk status.  Pulmonary angiogram studies or at least further clinical follow-up history would be useful.