Blood Gas Analysis

This study was a preplanned secondary analysis of a prospective registry of consecutive ED patients with severe sepsis with evidence of hypoperfusion treated with an institutional quantitative resuscitation protocol that is initiated in the ED at the time of recognition of sepsis (18 (link)). This study protocol was reviewed and approved by the institutional review board for the conduct of human research before enrollment of patients.
Subjects were enrolled from November 2005 through October 2007 in the ED at Carolinas Medical Center, an 800-bed teaching hospital with 120,000 ED patient visits per year. Explicit criteria for enrollment included 1) age >17 years; 2) suspected or confirmed infection; 3) two or more systemic inflammatory response syndrome criteria (19 (link)): heart rate >90 beats per minute, respiratory rate >20 breaths per minute, temperature >38°C or <36°C, white blood cell count >12,000 or <4000 cells/mm³ or >10% bands; and 4) systolic blood pressure <90 mm Hg or mean arterial pressure <65 mm Hg after a isotonic fluid bolus and anticipated need for ICU care, or a serum lactate concentration ≥4.0 mmol/L and anticipated need for ICU care. Exclusion criteria included 1) age <18 years; 2) need for immediate surgery; and 3) absolute contraindication for a chest central venous catheter.
Eligible subjects were identified by board-certified emergency physicians and were treated in the ED and medical ICU with an institution-approved quantitative resuscitation protocol that was previously described (20 (link)). All data elements required for calculation of the SOFA score at the time of ED recognition and resuscitation (T0) and 72 hours after ICU admission (T72), as well as hospital outcomes, were prospectively collected on standardized forms and entered into a database for later analysis. For T0 scores, only data available in the ED were used for calculation; and for T72 scores, data available within 12 hours of the 72-hour time point were used for calculation. To our knowledge, no physician in the ED had any independent knowledge of the SOFA score. For purposes of this study, we made one modification in the calculation of the respiratory component of the SOFA score (Table 1). We preferentially used the PaO₂ to FIO₂ ratio (PaO₂/FIO₂) when arterial blood gases were obtained. In cases where the PaO₂ was not available, we used the peripheral arterial oxygen saturation (SaO₂) to FIO₂ ratio (SaO₂/FIO₂). This substitution has been previously validated with high correlation (21 (link)). The definitions of SOFA score variables were otherwise identical to those reported in the original publication by Vincent et al (17 (link)).

All MRI measurements were performed on a 3T Siemens Tim Trio system (Siemens Medical Solutions, Erlangen, Germany) using a 12-channel head coil. The cylindrical container was placed in the scanner with its long axis parallel to the B₀ field. A 2D gradient-recalled Echo (GRE) sequence was used to obtain axial phase maps with the following imaging parameters, voxel size: (voxel size =1×1×5 mm³, FOV = 76mm × 76 mm, flip angle = 25°, TE = 7.2ms, TR = 70ms, number of echoes = 2, echo spacing (ΔTE)= 2.5ms, total scan time ~11s). Phase difference (Δϕ) was computed by taking the difference of the phase images from the two echoes.
The susceptibility differences between various compartments (such as air, tissue etc.) cause field inhomogeneities and result in low spatial-frequency modulations of the phase signal. To minimize this interfering effect a retrospective correction method was implemented, which approximates the field inhomogeneity by a second-order polynomial. The compartments where oxygen saturation was to be determined were masked out and the phase difference image was weighted with the corresponding masked magnitude image. The robustness and accuracy of the method for quantifying susceptibility has been previously validated by some of the present authors (19 (link)). The experimental set-up, duplicated in the current work, consisted of an array of sample tubes filled with Gd-doped water of various concentrations and known volume susceptibilities.
The susceptibility difference (Δχ) between blood and water was computed from the phase difference (Δϕ) between an ROI placed inside the cross sectional area of each tube and the surrounding water as
$$\mathrm{\Delta }\chi =\frac{3\mathrm{\Delta }\varphi }{\gamma B_0\mathrm{\Delta }\mathit{\text{TE}}}$$
Δχ_do was obtained from the slope of Δχ/Hct, where Hct are the individual hematocrit levels, and the concentration of deoxy-Hb (1-HbO₂) obtained from blood gas analysis (Eq 2):
$$\frac{\mathrm{\Delta }\chi }{\mathit{\text{Hct}}}=\mathrm{\Delta }{\chi }_{\mathit{\text{do}}}\left(1-{\mathit{\text{HbO}}}_2\right)+\mathrm{\Delta }{\chi }_{\mathit{\text{oxy}}}$$
where Δχ_oxy is the susceptibility difference between fully oxygenated blood and water. In this model it is assumed that the χ_plasma~ χ_water (14 (link)).

Patients were seen every three months during years 1 and 2 post treatment and then every 6 months until 4 years post treatment. Imaging was required at each visit for response and toxicity assessment using CT scans. Follow-up PET scans were required if progressive soft tissue abnormalities where noted on CT. Pulmonary function tests (FEV-1, DLCO, and arterial blood gases) were to be performed every 3 months for year 1 posttreatment and every 6 months for year 2 post treatment. Tumor measurements at each follow-up were carried out using the Response Evaluation Criteria in Solid Tumors (RECIST)12 (link) where a complete response (CR) is total tumor disappearance and partial response (PR) is decrease in the longest tumor diameter by 30% or more.
The primary endpoint of the study was two-year actuarial primary tumor control. Primary tumor control was defined as the absence of primary tumor failure. Primary tumor failure was defined based on meeting both of two criteria: 1. Local enlargement defined as at least a 20% increase in the longest diameter of the gross tumor volume per CT, and 2. Evidence of tumor viability. Tumor viability could be affirmed by either demonstrating PET imaging with uptake of a similar intensity as the pretreatment staging PET, or by repeat biopsy confirming carcinoma. Primary tumor failure included marginal failures occurring within 1 cm of the planning target volume (1.5-2.0 cm from the gross tumor volume). Failure beyond the primary tumor but within the involved lobe was collected separately from disseminated failure within uninvolved lobes. Local failure is the combination of primary tumor and involved lobe failure with local control being the absence of local failure.
Secondary endpoints included assessments of treatment-related toxicity, disease free survival and overall survival. Disease-free survival included separate assessments of local-regional failure (within the primary site, involved lobe, hilum, and mediastinum) and disseminated recurrence (failure beyond the local and regional sites).
The National Cancer Institute’s Common Toxicity Criteria (CTC) Version 3.0 was used for grading of adverse events13 (link). Certain adverse events attributable to study therapy were specified prospectively within the protocol for use in evaluating the secondary endpoint of treatment related toxicity including grade 3 measures of lung injury, esophageal injury, heart injury, and nerve damage as well as any grade 4-5 toxicity felt related to treatment. However, all adverse events reported by participating centers were collected and assessed.