Possible Intergel Reaction Syndrome (pIRS)

To the Editor:

The recent report by Tang et al¹ heightens concerns about the effects of Intergel (ferric hyaluronate, FeHA) and the mechanism of what has been termed “Intergel Belly”⁶ or “possible Intergel Reaction Syndrome” (pIRS).²

The authors sought to examine the effect of Intergel in 700 patients undergoing colorectal surgery and ileostomy reversal. After 32 patients, the study was terminated because of unacceptably high morbidity: Intergel was associated with prolonged ileus and “predisposed to the development of late postoperative peritonitis and anastomotic dehiscence.” There was one death in the control group due to myocardial infarct secondary to a postoperative bleed. With Intergel, 1 patient developed pulmonary embolism after relaparotomy for dehiscence and subsequently died.

Despite the availability of these data in 2001,³ the package label continued in both U.S.⁴ and international versions to state that Intergel “has not been studied…in patients having surgery which involves opening of the gastrointestinal or urinary tract,” and remained silent on the issue of contamination.

The availability of these data might well have prevented at least 2 deaths in patients where Intergel was used and where the bowel had been perforated. According to an account given to a leading patient group,⁵ surgeons thought that the postoperative pain in these patients may have been related to the “late onset, postoperative pain following use of the device” as well as “noninfectious peritoneal inflammation,” described in a company announcement. Not considering infection to be another cause of pain, its treatment was delayed, and patients died.

Tang et al note their caution. They appropriately considered the increase in mortality due to FeHA in inoculated rats⁶ and considered conclusions from a similar study⁷ that “intraperitoneal administration of INTERGEL Adhesion Prevention Solution at dose volumes up to 15 mL/kg does not potentiate mortality or abscessformation following bacterially induced peritonitis.” However, this conclusion, made despite a numerical increase in mortality from 25% to 45% (high-dose FeHA), may have been subject to a type II error.

The study was repeated with 60 animals per group⁸: mortality in control (37%) and Intergel (40%) groups was comparable, but the conclusion that “placement of 5 mL/kg Intergel Solution in the peritoneal cavity concurrently with a bacterial inoculum did not affect the course of host resistance to the infection” was flawed because:

1. Unlike the previous study, no positive control (dextran) was used to demonstrate that this notoriously difficult model was capable of detecting potentiation of infection.

2. Only the lower of the 2 doses (1× human dose equivalent) was retested (15%–25% increase in mortality, previously). The 3× dose (25%–45% increase in mortality, previously) was omitted.

3. Inocula were frozen not in bulk (as in the Tzianabos study⁶) but as single doses. Bacterial virulence is more likely to be lost using the latter method, but in either event its variable preservation necessitates the use of a positive control in every experiment.

4. In the first study, the reduction in the abscesses in INTERGEL-treated animals was considered to support the (erroneous) conclusion regarding infection potentiation. However, since abscess formation was only assessed in surviving animals, the increased mortality observed in INTERGEL-treated animals resulted in a selection bias with regard to abscess assessment. When similar mortality rates were observed in the repeated study, there was no change in abscess rates.⁸

Tang et al do not appear to have had the opportunity to review with their supporters’ even earlier data which, it seems, have emerged not in the regulatory record, nor in the scientific literature, but in plaintiff's discovery.² This low-powered study (15 animals per group) also showed a nonstatistically significant increase (40%–67%) in mortality with high-viscosity FeHA compared dose for dose with the low viscosity equivalent, or Ringer's lactate.

A number of reported effects of FeHA in animals may also illuminate the mechanism(s) of pIRS: dystrophic calcification in rabbits, granulomatous peritonitis in rats, an increased death rate in rats following severe peritoneal trauma applied laparoscopically, and a possible reduction in Intergel's efficacy in a bleeding field.² Clinical findings may further clarify the mechanisms of pIRS: the lack of efficacy (in laparoscopy) in endometriosis patients in whom there was also an associative trend of reactivity;² an increase in the rate of infection;⁴ a trend toward more reactivity in patients undergoing extensive surgery;² changes in lymphocyte, neutrophil, and basophil counts;⁹ and shifts in calcium levels.⁹

Intergel contains both iron and ammonia. The toxicity and role of iron in a variety of pathologic processes including free-radical generation, carcinogenesis, and asbestosis has been extensively described. The contribution of iron hydroxide particulates found in the Intergel to pIRS has not been determined. Iron in vitro has been shown to be toxic to mouse peritoneal macrophages via an oxidative mechanism, at a concentration almost 70 times¹⁰ lower than that found in Intergel.¹¹ Intergel toxicity may also be mediated via its ammonia content, which is similar to or exceeds that required to compromise macrophage¹² or lymphocyte function¹³ in vitro.

These comments are not intended to criticize Tang et al. I have every confidence based on their responsible actions that, had they had full access to data and analyses existent prior to their study, they would either have not initiated it or, would have exercised even greater caution, and would have not agreed to their sponsor's requests to delay publication of their data.³ Arguably, this may have helped avoid later adverse events.

I commend the authors for their account and anticipate that it will contribute to a determination of the mechanism of pIRS, its possible long-term sequelae and treatment; as well to a heightened caution regarding the planned reintroduction of Intergel.

David M. Wiseman, PhD, MRPharmS
Synechion, Inc., International Adhesions Society, Ethicon, Inc. (formerly), and Johnson & Johnson Medical, Inc. (formerly)
Dallas, TX
david.wiseman@adhesions.org