Thurs., 10/16/08 Tibia/Polytrauma, Paper #14, 4:44 pm OTA-2008
Δ Preoperative Hypertonic Saline Attenuates Postoperative Neutrophil Priming following Reamed Intramedullary Nailing of Isolated Femur Shaft Fractures
Philip F. Stahel, MD1 (n); Wade R. Smith, MD1 (a-OTA Grant); Juan F. Agudelo, MD1 (n);
Allison E. Williams, RN3 (n); Ernest E. Moore, MD2 (n); Philip C. Eckels2 (a-OTA Grant);
Steve J. Morgan, MD1 (a-OTA Grant);
1Departments of Orthopaedics, Denver Health Medical Center, University of Colorado
School of Medicine, Denver, Colorado, USA;
2Denver VA Medical Center, Denver, Colorado, USA;
3Department of Surgery, Denver Health Medical Center, University of Colorado
School of Medicine, Denver, Colorado, USA
Purpose: Femoral reaming and intramedullary nailing (IMN) can prime polymorphonuclear neutrophils (PMNs) and increase the posttraumatic systemic inflammatory response. Hyperosmolar resuscitation with hypertonic saline (HTS) has been shown to attenuate PMN priming after trauma. We hypothesized that the preoperative administration of HTS (7.5%) would attenuate the extent of PMN priming in patients undergoing IMN fixation of isolated femoral shaft fractures, compared to control patients treated with normal saline (0.9%) (NS).
Methods: In this prospective, randomized, double-blind study performed at a Level 1 trauma center, inclusion criteria were age >18 years, isolated femur shaft fractures amenable to IMN fixation within 24 hours after injury, and an Injury Severity Score (ISS) <25. The study was IRB-approved. Patients were randomized prior to surgery into treatment group (7.5% HTS) or placebo group (0.9% NS). Study drugs were administered in a blinded bag as a single bolus of 4 mL/kg immediately prior to surgery. Whole blood samples were collected at baseline, before study drug application, and at the time points 6, 12, and 24 hours after surgery. Isolated PMNs were analyzed by flow cytometry for cell surface expression levels of CD11b (the alpha-chain of complement receptor type 3), CD62L (L-selectin), and CD66b, a granulocyte-specific cell marker. Differences in expression levels were determined after ex vivo preincubation with recombinant platelet-activating factor (PAF), a mediator of PMN priming. The mean fluorescence intensity (MFI) levels were used for quantification of cell surface molecule expression. A repeated-measures analysis of variance was used for analysis of differences between time-points and between the groups. A P value <0.05 was considered statistically significant.
Results: 20 patients were enrolled and allocated to equally sized treatment groups (n = 10 per group). Groups were matched by age and gender and had equal ISS scores, ranging from 9 to 16 points. Baseline expression of CD11b, CD62L, and CD66b cell markers was in a similar range between the two groups (saline control: 4.26/6.76/1.16 MFI, HTS: 5.46/8.65/1.285 MFI). After femoral IMN, the extent of PMN priming appeared to be significantly attenuated within 24 hours in the HTS group, compared to the NS group. The ex vivo PAF preincubation revealed significant differences between unstimulated versus PAF-stimulated cell surface marker expression levels in the two groups at 24 hours (P <0.01 for each cell marker, HTS vs saline). The ΔMFI levels of CD11b and CD66b were significantly higher in the NS group (5.75 and 1.13, respectively; ΔPAF-stimulated, -unstimulated median levels) compared to the HTS group (4.77 and 0.76, respectively; P <0.01) at 24 hours. Reciprocally, the differences in CD62L levels were significantly lower in the NS group, as a sign of L-selectin shedding from cell surfaces (–1.23 vs –0.076, NS vs HTS; ΔPAF-stimulated, -unstimulated median levels), at 24 hours.
Conclusion and Significance: The preoperative infusion of HTS appears to exert a strong immunomodulation by attenuating the extent of posttraumatic and postoperative PMN priming. The differences in PAF-induced cell surface expression levels of CD11b and CD66b were significantly lower in the HTS group. In addition, the shedding of L-selectin, as an indirect sign of immunoactivation, was significantly reduced in the HTS group, compared to saline controls. These data provide a scientific rationale for a strong immunomodulatory role of HTS by attenuating the hyperinflammatory responses related to PMN priming in patients undergoing IMN of femur fractures. Future clinical studies will have to determine whether these anti-inflammatory effects detected at the cellular level may be beneficial for patients with femur shaft fractures by reducing the extent of pulmonary and systemic complications.
If noted, the author indicates something of value received. The codes are identified as a-research or institutional support; b-miscellaneous funding; c-royalties; d-stock options; e-consultant or employee; n-no conflicts disclosed, and *disclosure not available at time of printing.
• The FDA has not cleared this drug and/or medical device for the use described in this presentation (i.e., the drug or medical device is being discussed for an “off label” use). ◆FDA information not available at time of printing. Δ OTA Grant.