How strong is the evidence for IV contrast-induced nephropathy (CIN) following CT scans?

Not as strong as one might expect with an increasing number of investigators questioning the causative role of IV contrast in precipitating CIN.

A 2013 meta-analysis involving observational—mostly retrospective— studies concluded that the risks of AKI, death, and dialysis were similar between IV contrast and non-contrast patients, including those with diabetes or underlying renal insufficiency1.

Two retrospective studies2,3 designed to control for a variety of factors that may affect the risk of AKI by propensity matching found divergent results with the larger and better designed study finding no significant difference in AKI between the 2 groups3. A 2017 retrospective cohort analysis of emergency department patients utilizing a similar propensity-score analysis also failed to find a difference in post-CT AKI between those receiving and not receiving IV contrast4.

Further shedding doubt on the role of IV contrast in causing AKI, a study involving patients with chronic kidney disease found no difference in the rates of excretion of 2 biomarkers of AKI (neutrophil gelatinase-associated lipocalin-NGAL, and kidney injury molecule-1-KIM-1) between patients with and without presumed CIN5. Some have even criticized experimental animal studies supporting the existence of CIN due to their poor applicability to human renal disease1.

This is not to say that IV CIN does not exist. Rather, we should keep an open mind about the pathophysiology and epidemiology of CIN. Stay tuned!

Fun pearl: Did you know that the first case of CIN was described in a patient with multiple myeloma undergoing IV pyelography (before the CT era)?

References

  1. McDonald JS, McDonald RJ, Comin J, et al. Frequency of acute kidney injury following intravenous contrast medium administration: a systematic review and meta-analysis. Radiology. 2013;267(1):119-128. https://www.ncbi.nlm.nih.gov/pubmed/23319662
  2. Davenport MS, Khalatbari S, Dillman JR, et al. Contrast material-induced nephrotoxicity and intravenous low-osmolality iodinated contrast material. Radiology. 2013;267(1):94-105. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3606541/pdf/121394.pdf
  3. McDonald RJ, McDonald JS, Bida JP, et al. Intravenous contrast material-induced nephropathy: causal or coincident phenomenon? Radiology 2013;267:106-18. https://www.ncbi.nlm.nih.gov/pubmed/23360742
  4. Hinson JS, Ehmann MR, Fine DM, et al. Risk of acute kidney injury after intravenous contrast media administration. Ann Emerg Med 2017; 69:577-586. https://www.ncbi.nlm.nih.gov/pubmed/28131489
  5. Kooiman J, van de Peppel WR, Sijpkens YWJ, et al. No increase in kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin excretion following intravenous contrast enhanced-CT. Eur Radio 2015;25:1926-34. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4457910/pdf/330_2015_Article_3624.pdf

Contributed by Ginger Jiang, Medical Student, Harvard Medical School

How strong is the evidence for IV contrast-induced nephropathy (CIN) following CT scans?

When evaluating for an esophageal perforation, is a water-soluble contrast agent such as Gastrografin a better and safer alternative to barium swallow study?

Water-soluble contrast agents (WCAs) (eg, meglumine diatrizoate or Gastrografin) are often ordered as the initial radiographic test for evaluation of esophageal perforation or leaks, followed by barium swallow if the test is negative because small leaks are better detected with the more radiopaque barium1.  Such practice, however, is based on extrapolation of data on the deleterious effect of barium when extravasated into the peritoneal cavity, not the mediastinum1.   In fact, clinical evidence linking mediastinitis to extravasated barium is lacking, and even in experimental studies, injection of barium into the mediastinum of cats have failed to cause clinically significant mediastinitis2.

When ordering a contrast swallow study, no medium should be considered totally safe or effective in detecting esophageal perforations or leaks and WCAs are no different. Potential disadvantages of WCAs include: 1. Inferior sensitivity (as low as 50%)—due to decreased radio-opacity—when compared to barium3; 2. Risk of pulmonary edema—occasionally lethal— when aspirated into the lung due to high osmolality (analogous to salt water drowning) and intense inflammatory reaction4,5; 3. Contraindication in the setting of tracheoesophageal fistula,6; 4. Risk of serious allergic reaction due to reabsorption of iodinated compounds1; and 5. Added exposure to radiation and cost of testing when the swallow study is repeated with barium.  For these reasons, the standard practice of an initial WCA followed by a barium swallow`study if the former is negative, has been questioned, with some centers foregoing the WCA study altogether in favor of barium swallow in certain patients 1,6.

In short, when evaluating for esophageal perforation, WCAs should not categorically be considered a “better” or “safer” alternative to barium; in certain situations, barium may be the preferred agent. When in doubt, input from a thoracic surgeon is recommended.  

 

References

  1. Gollub MJ, Bains MS. Barium sulfate: a new (old) contrast agent for diagnosis of postoperative esophageal leaks. Radiology 1997;202:360-62. https://www.ncbi.nlm.nih.gov/pubmed/9015057
  2. James AE, Montali RJ, Chaffee V, et al. Barium or gastrografin: which contrast media for diagnosis of esophageal tears? Gastroenterology 1975;68:1103-1113. https://www.ncbi.nlm.nih.gov/pubmed/1126592
  3. Berry BE, Ochsner JL. Perforation of the esophagus: a 30 year review. J Thorac Cardiovasc Surg 1973;65:1-7. http://www.jpedsurg.org/article/0022-3468(73)90248-0/abstract
  4. Trulzsch DV, PenmetsaA, Karim A, et al. Gastrografin-induced aspiration pneumonia: A lethal complication of computed tomography. South Med J 1992;85:1255-56. https://www.ncbi.nlm.nih.gov/pubmed/1470976
  5. Tuladhar R, Patole S, Whitehall J. Gastrografin aspiration in a neonate with tracheoesophageal fistula. J Paediatr Child Health 2000; 36:94-6. https://www.ncbi.nlm.nih.gov/pubmed/10723703
  6. FDA https://www.drugs.com/pro/gastrografin.html.
  7. Roh S, Iannettoni MD, Keech JC, et al. Role of barium swallow in diagnosing clinically significant anastomotic leak following esophagectomy. Korean J Thorac Cardiovasc Surg 2016;49:99-109. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4825910/pdf/kjtcv-49-099.pdf

 

When evaluating for an esophageal perforation, is a water-soluble contrast agent such as Gastrografin a better and safer alternative to barium swallow study?

Should I be concerned about piperacillin-tazobactam nephrotoxicity in the absence of vancomycin?

Nephrotoxicity associated with piperacillin-tazobactam (PT) combined with vancomycin (V) has been increasingly reported1,2,  with  some recommending that an alternative to V be used when PT is also on board 2. However, there are several reasons why the nephrotoxic potential of PT either alone or with antibiotics other than V also deserves further study before such recommendations can be widely embraced3.

First, most studies of VPT combination do not include comparative V or PT alone arms making it difficult to assess the relative contribution of these 2 antibiotics to kidney injury when used in combination. A small study that did include a PT-only  arm reported a similar rate of acute kidney injury (AKI) in PT and VPT arms ( 15.4% and 18.8% , respectively), both significantly higher that than of  V-only group (4%).4

 Other reasons not to readily dismiss PT as a cause of nephrototoxicity include the  lack of association between higher V trough levels and AKI in patients receiving VPT2, the association of PT with lower rates of renal function recovery in critically ill patients when compared to other selected β-lactams5,  and higher magnesium and potassium renal tubular loss with the use of PT compared to selected cephalosporins and ciprofloxacin6.  As with other penicillins, PT-associated acute interstitial nephritis may also occur7-8.

In short, even in the absence of V, nephrotoxic potential of PT should not be automatically dismissed.

 

Disclosure: Ref 3 was also authored by the creator of this pearl.

References

  1. Hammond DA, Smith MN, Chenghui Li, et al. Systematic review and meta-analysis of acute kidney injury associated with concomitant vancomycin and piperacillin/tazobactam. Clin Infect Dis 2017;64:666-74.
  2. Navalkele B, Pogue JM, Karino S, et al. Risk of acute kidney injury in patients on concomitant vancomycin and piperacillin-tazobactam compared to those on vancomycin and cefepime. Clin Infect Dis 2017;64:116-123.
  3. Manian FA. Should we revisit the nephrotoxic potential of piperacillin-tazobactam as well? Clin Infect Dis 2017; https://doi.org/10.1093/cid/cix321
  4. Kim T, Kandiah S, Patel M, et al. Risk factors for kidney injury during vancomycin and piperacillin/tazobactam administration, including increased odds of injury with combination therapy. BMC Res Notes 2015;8:579.
  5. Jensen J-U S, Hein L, Lundgren B, et al. Kidney failure related to broad-spectrum antibiotics in critically ill patients: secondary end point results from a 1200 patient randomized trial. BMJ Open 2012;2:e000635. http://bmjopen.bmj.com/content/2/2/e000635
  6. Polderman KH, Girbes ARJ. Piperacillin-induced magnesium and potassium loss in intensive care unit patients. Intensive Care Med 2002;28:530-522.
  7. Muriithi AK, Leung N, Valeri AM, et al. Clinical characteristics, causes and outcomes of acute interstitial nephritis in the elderly. Kidney International 2015;87:458-464.
  8. Soto J, Bosch JM, Alsar Ortiz MJ, et al. Piperacillin-induced acute interstitial nephritis. Nephron 1993;65:154-155. 
Should I be concerned about piperacillin-tazobactam nephrotoxicity in the absence of vancomycin?

What complications should I look for in my hospitalized patient suspected of having check-point inhibitor toxicity?

Targeting the host immune system via monoclonal antibodies known as checkpoint inhibitors (CPIs) is an exciting new strategy aimed at interfering with the ability of cancer cells to evade the patient’s existing antitumor immune response. CPIs have been shown to be effective in a wide variety of cancers and are likely to be the next major breakthrough for solid tumors1-3. Unfortunately, serious—at times fatal— immune-related Adverse Events (irAEs) have also been associated with their use4,5.

IrAEs occur in the majority of patients treated with nivolumab (a programmed death 1 [PD-1] CPI] or ipilimumab (a cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4] CPI)1. The severity of irAEs may range from mild (grade 1) to very severe (grade 4). Grading system categories discussed in more detail at link below:

https://www.eortc.be/services/doc/ctc/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf.

Although fatigue, diarrhea, pruritis, rash and nausea are not uncommon, more severe grade (3 or 4) irAEs may also occur (Figure). The most frequent grade 3 or 4 irAEs are diarrhea and colitis; elevated ALT or AST are also reported, particularly when CPIs are used in combination. Hypophysitis, thyroiditis, adrenal insufficiency, pneumonitis, enteritis sparing the colon with small bowel obstruction, and hematologic and neurologic toxicities may also occur.

Generally, skin and GI toxicities appear first, within a few weeks of therapy, followed by hepatitis and endocrinopathies which usually present between weeks 12 and 245. High suspicion and early diagnosis is key to successful management of irAEs.

Figure. Selected irAEs associated with nivolumab and ipilimumab (adapted from reference 1).

chceky2

References

  1. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23-34.
  2. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373:1627-1639.
  3. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015; 373:123-135.
  4. Weber JS, Yang JC, Atkins MB, Disis ML. Toxicities of immunotherapy for the practitioner. J Clin Oncol 2015;33:2092-2099.
  5. Weber JS. Practical management of immune-related adverse events from immune checkpoint protein antibodies for the oncologist. Am Soc Clin Oncol Educ Book. 2012:174-177.

Contributed by Kerry Reynolds, MD, Mass General Hospital, Boston.

 

 

 

 

What complications should I look for in my hospitalized patient suspected of having check-point inhibitor toxicity?

Is the combination of piperacillin-tazobactam and vancomycin (PT-V) nephrotoxic?

Despite its widespread use for over 20 years, PT-V has only recently been linked to higher risk of AKI when compared to vancomycin+/- other β-lactams, particularly cefepime1,2.  A 2016 meta-analysis of 14 observational studies reported an AKI incidence ranging from 11%-48.8% for PT-V (used for ≥48 h in most studies), with an adjusted O.R. of 3.11 (95% C.I. 1.77-5.47) when compared to other vancomycin treatment groups1.  Of note, nephrotoxicity associated with PT-V appears to occur earlier than the comparative groups (median 3 days vs 5 days of therapy, respectively), with the highest daily incidence observed on days 4 and 52.

Although the exact mechanism(s) of nephrotoxicity in patients receiving PT-V is unknown, both piperacillin and vancomycin have been implicated in acute renal tubular dysfunction/necrosis and acute interstitial nephritis3-5.

Collectively, these findings are only a reminder to be more judicious in the selection and duration of treatment of even “safe” antibiotics.

 

References

  1. Hammond DA, Smith MN, Chenghui Li, et al. Systematic review and meta-analysis of acute kidney injury associated with concomitant vancomycin and piperacillin/tazobactam. Clin Infect Dis 2016 ciw811.doi:10.1093cid/ciw811.
  2. Navalkele B, Pogue JM, Karino S, et al. Risk of acute kidney injury in patients on concomitant vancomycin an dpiperacillin-tazobactam compared to those on vancomycin and cefepime. Clin Infect Dis 2017;64:116-123.
  3. Hayashi T, Watanabe Y, Kumano K, et al. Pharmacokinetic studies on the concomitant administration of piperacillin and cefazolin, and piperacillin and cefoperazone in rabbits. J Antibiotics 1986; 34:699-712.
  4. Polderman KH, Girbes ARJ. Piperacillin-induced magnesium and potassium loss in intensive care unit patients. Intensive Care Med 2002;28:530-522.
  5. Htike NL, Santoro J, Gilbert B, et al. Biopsy-proven vancomycin-associated interstitial nephritis and acute tubular necrosis. Clin Exp Nephrol 2012;16:320-324.
Is the combination of piperacillin-tazobactam and vancomycin (PT-V) nephrotoxic?

What are the benefits and risks of inhaled dual anticholinergic therapy (IDAT) in patients admitted to the hospital with a diagnosis of acute exacerbation of chronic obstructive pulmonary disease (AECOPD)?

Patients admitted with AECOPD are commonly on maintenance tiotropium and are frequently treated with additional inhaled anticholinergic agents (eg, ipratropium) during hospitalization. However, the scientific evidence justifying IDAT in patients with AECOPD is lacking, and is quite limited even in patients with stable COPD1-3.   Two small, randomized double-blind studies compared the impact of tiotropium combined with either ipratropium or placebo in outpatients with stable COPD.  Both studies selected FEV1 alone as their primary end-point and found only a marginal benefit with IDAT2,3

A population-based study of acute urinary retention in persons with COPD aged ≥66 years found a significantly higher odds of acute urinary retention among those on IDAT vs monotherapy or no anticholinergics (odds ratios 1.4 and 2.7, respectively)4.

In short, routine use of IDAT in patients with AECOPD lacks firm evidence in its clinical efficacy and may be associated with acute urinary retention.

 

References                                                                                                                                                               

 

  1. Cole JM, Sheehan AH, Jordan JK. Concomitant use of ipratropium and tiotropium in chronic obstructive pulmonary disease. Ann Pharmacother 2012;46:1717-21.
  2. Kerstjens HA, Bantje TA, Luursema PB, Sinninghe Damste HE, de Jong JW. Effects of short-acting bronchodilators added to maintenance tiotropium therapy. Chest 2007;132:1493-9.
  3. Cazzola M, Santus P, D’Adda A, et al. Acute effects of higher than standard doses of salbutamol and ipratropium on tiotropium-induced bronchodilation in patients with stable COPD. Pulm Pharmacol Ther 2009; 22:177-82.
  4. Singh S, Furbergt CD. Inhaled anticholinergic drug therapy and the risk of acute urinary retention in chronic obstructive pulmonary disease. Arch Intern Med 2011;171:920-2.

 

Contributed by Josh Ziperstein, MD, Massachusetts General Hospital, Boston.

What are the benefits and risks of inhaled dual anticholinergic therapy (IDAT) in patients admitted to the hospital with a diagnosis of acute exacerbation of chronic obstructive pulmonary disease (AECOPD)?

My patient on methadone complains of lower extremity edema. Could they be related?

Yes! As early as 1979, case series of patients on methadone developing peripheral edema within 3-6 months of therapy appeared in the literature1.  Subsequent studies revealed that edema may develop from 1 week  to 6 months or longer following initiation of methadone, its severity is dose-dependent, and that it improves with reduction of methadone dose or discontinuation of therapy.  Distal extremities or the face are often involved; pulmonary edema may also occur1-3.  It is often resistant to diuretics.

The mechanism by which methadone causes peripheral edema is unclear but several hypotheses have been forwarded. The high volume of distribution and accumulation of methadone in tissues results in higher oncotic pressures in the extravascular space which in combination with reduced oncotic pressures in blood vessels due to venodilatation may lead to edema.  Other potential mechanisms include opioid-induced histamine release directly from mast cells causing venous permeability, and opioid-induced secretion of antidiuretic hormone 1-3.  

 

References

  1. Dawson C, Paterson F, McFatter F, Buchanan D. Methadone and oedema in the palliative care setting: a case report and review of the literature. Scottish Med J 2014;59: e-11-e14.
  2. Mahè I, Chassany O, Grenard A-S, Caulin C, Bergmann J-F. Methadone and edema: a case-report and literature review. Eur J Clin Pharmacol 2004;59:923-924. \
  3. Kharlamb V, Kourlas H. Edema in a patient receiving methadone for chronic low back pain. Am J Health-Syst Pharm 2007;64:2557-60.

 

My patient on methadone complains of lower extremity edema. Could they be related?