Chronic Intermittent Hypoxia Is Independently Associated with Reduced Postoperative Opioid Consumption in Bariatric Patients Suffering from Sleep-Disordered Breathing

<div><p>Background</p><p>Evidence suggests that recurrent nocturnal hypoxemia may affect pain response and/or the sensitivity to opioid analgesia. We tested the hypothesis that nocturnal hypoxemia, quantified by sleep time spent at an arterial saturation (SaO₂) < 90% and minimum nocturnal SaO₂ on polysomnography, are associated with decreased pain and reduced opioid consumption during the initial 72 postoperative hours in patients having laparoscopic bariatric surgery.</p><p>Methods</p><p>With Institutional Review Board approval, we examined the records of all patients who underwent laparoscopic bariatric surgery between 2004 and 2010 and had an available nocturnal polysomnography study. We assessed the relationships between the time-weighted average of pain score and total opioid consumption during the initial 72 postoperative hours, and: (a) the percentage of total sleep time spent at SaO₂ < 90%, (b) the minimum nocturnal SaO₂, and (c) the number of apnea/hypopnea episodes per hour of sleep. We used multivariable regression models to adjust for both clinical and sleep-related confounders.</p><p>Results</p><p>Two hundred eighteen patients were included in the analysis. Percentage of total sleep time spent at SaO₂ < 90% was inversely associated with total postoperative opioid consumption; a 5-%- absolute increase in the former would relatively decrease median opioid consumption by 16% (98.75% CI: 2% to 28%, P = 0.006). However, the percentage of total sleep time spent at SaO₂ < 90% was not associated with pain. The minimum nocturnal SaO₂ was associated neither with total postoperative opioid consumption nor with pain. In addition, neither pain nor total opioid consumption was significantly associated with the number of apnea/hypopnea episodes per hour of sleep.</p><p>Conclusions</p><p>Preoperative nocturnal intermittent hypoxia may enhance sensitivity to opioids.</p></div

Secondary results for the apnea /hypopnea index and OSA diagnosis ^*(N = 218).

<p>Secondary results for the apnea /hypopnea index and OSA diagnosis ^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0127809#t003fn001" target="_blank">*</a>}(N = 218).</p

Flow diagram for the selection of eligible cases.

<p>Flow diagram for the selection of eligible cases.</p

Primary results for the nocturnal arterial saturation status. ^*(N = 218).

<p>Primary results for the nocturnal arterial saturation status. ^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0127809#t002fn001" target="_blank">*</a>}(N = 218).</p

Morphometrics, clinical characteristics, and polysomnography variables (N = 218^*).

<p>Morphometrics, clinical characteristics, and polysomnography variables (N = 218^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0127809#t001fn001" target="_blank">*</a>}).</p

Boxplots of time-weighted average pain scores (11-point verbal numerical rating scale; 0–10) and of total opioid consumption in mg of intravenous morphine equivalent dose obtained at 4 discrete postoperative intervals (0–12, 1–24, 0–48, and 0–72 hours after surgery) for the 218 patients included in the analysis.

<p>The first quartile, median, and third quartile comprise the boxes; whiskers extend to the most extreme observations within 1.5 times the interquartile range of the first and third quartiles, respectively; points outsides these whiskers are displayed individually. IV = intravenous.</p

Hypomorphic and dominant-negative impact of truncated SOX9 dysregulates Hedgehog-Wnt signaling, causing campomelia.

Haploinsufficiency for SOX9, the master chondrogenesis transcription factor, can underlie campomelic dysplasia (CD), an autosomal dominant skeletal malformation syndrome, because heterozygous Sox9 null mice recapitulate the bent limb (campomelia) and some other phenotypes associated with CD. However, in vitro cell assays suggest haploinsufficiency may not apply for certain mutations, notably those that truncate the protein, but in these cases in vivo evidence is lacking and underlying mechanisms are unknown. Here, using conditional mouse mutants, we compared the impact of a heterozygous Sox9 null mutation (Sox9+/-) with the Sox9+/Y440X CD mutation that truncates the C-terminal transactivation domain but spares the DNA-binding domain. While some Sox9+/Y440X mice survived, all Sox9+/- mice died perinatally. However, the skeletal defects were more severe and IHH signaling in developing limb cartilage was significantly enhanced in Sox9+/Y440X compared with Sox9+/-. Activating Sox9Y440X specifically in the chondrocyte-osteoblast lineage caused milder campomelia, and revealed cell- and noncell autonomous mechanisms acting on chondrocyte differentiation and osteogenesis in the perichondrium. Transcriptome analyses of developing Sox9+/Y440X limbs revealed dysregulated expression of genes for the extracellular matrix, as well as changes consistent with aberrant WNT and HH signaling. SOX9Y440X failed to interact with β-catenin and was unable to suppress transactivation of Ihh in cell-based assays. We propose enhanced HH signaling in the adjacent perichondrium induces asymmetrically localized excessive perichondrial osteogenesis resulting in campomelia. Our study implicates combined haploinsufficiency/hypomorphic and dominant-negative actions of SOX9Y440X, cell-autonomous and noncell autonomous mechanisms, and dysregulated WNT and HH signaling, as the cause of human campomelia