Pamidronate Linked to Greater Likelihood for Survival, Ventilator Liberation in Chronic Critical Illness

Commentary by Rifka Schulman, MD

Cross Section of the Human KidneyUse of the intravenous bisphosphonate pamidronate for bone hyperresorption in chronic critical illness was associated with improved outcomes, including mortality and ventilator liberation, in patients with chronic critical illness and normal renal parameters, according to retrospective case study by Schulman et al presented at the American Association of Clinical Endocrinologists 24th Annual Scientific & Clinical Congress in Nashville, Tennessee, from May 13 to 17, 2015.

While impaired renal function is considered a barrier to use of bisphosphonates, the researchers found that measures of renal function remained stable or improved slightly following use of pamidronate.

“This study adds to the small but growing evidence base surrounding chronic critical illness and adds important knowledge regarding metabolic management of this complex and poorly understood population,” said Rifka Schulman, MD, Assistant Professor of Medicine at Long Island Jewish Medical Center, New Hyde Park, NY.

Defining Chronic Critical Illness
Patients with chronic critical illness undergo a prolonged course involving the need for prolonged mechanical ventilation and tracheostomy, Dr. Schulman said. Fewer than 50% of patients with chronic critical illness are liberated from the ventilator, and those who do survive have very poor quality of life, Dr. Schulman noted.

Chronic critical illness is typically incited by sepsis, trauma, or surgery that causes patients to have an adaptive stress response (ie, stress hormones, stress hyperglycemia, catabolic state). From an evolutionary perspective, this response is beneficial in the short-term for the survival of the organism. However, with the advent of many technological innovations in the ICU and patients being kept alive for longer periods, and these adaptations are no longer considered beneficial, Dr. Schulman explained. When patients develop chronic critical illness, a characteristic phenotype emerges involving multiorgan dysfunction characterized by ventilator dependence, poor nutritional state, catabolism, impaired wound healing, stress hyperglycemia, and elevated bone resorption.

Study Design
Previous findings from this research group demonstrated that pamidronate and ibandronate help reverse bone hyperresportion in this population.1,2 In the present study, the researchers examined whether use of pamidronate to treat hyperresorption could improve other clinical outcomes, including mortality, ventilator liberation, and renal function.

The study involved 148 patients with chronic critical illness at Mt. Sinai Hospital Respiratory Care Unit who were (n=30) or were not (n=118) treated with intravenous pamidronate (30-90 mg). Both groups included patients with normal renal function and those with varying levels of chronic kidney disease. In addition, all patients received calcium carbonate, ergocalciferol, and calcitriol, unless they had a contraindication.

Lower Rates of Mortality Found in Pamidronate Group
The pamidronate group had significantly lower rates of mortality in the respiratory care unit and at 1 year (Table). Pamidronate treatment was also linked to a greater likelihood of ventilator liberation (hazard ratio, 1.9), with the P value approaching statistical significance (P=0.1088), Dr. Schulman said.

Patients who received pamidronate had a lower hypoglycemia rate (ie, number of events per days in the RCU) compared with the group that did not receive pamidronate (0.09 vs. 0.12; P=00.71). After adjusting the analysis by the number of hypoglycemic events, the researchers found that patients who received pamidronate had the same risk for death in the RCU compared with those who did not receive pamidronate, but were significantly less likely to expire at 1 year (P=0.0018).

“For the short-term mortality, there was no longer a mortality improvement once [the analysis] was adjusted for hypoglycemia, implying that the hypoglycemia might be very connected to the improved mortality in the short-term. The long-term mortality remained significant, so there may be other factors in the long-term active pamidronate contributing to the improved mortality,” Dr. Schulman said.

Renal Parameters Remained Stable in Pamidronate Group
Assessment of renal outcomes, creatinine levels among patients who received pamidronate were significantly lower on day 7 and day 9 after treatment initiation, and were not statistically different from baseline levels by day 14. Serum albumin levels were similar at baseline (2.49 and 2.43 g/dL with and without pamidronate, respectively), but were significantly increased at the time of discharge in the pamidronate group (3.2 g/dL and 2.6 g/dL, respectively; P=0.0007). In addition, the glomerular filtration rate did not significantly change in the pamidronate group.

Dr. Schulman noted that prospective studies of pamidronate would be needed to confirm the findings.

September 22, 2015

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