Patient Inclusion Criteria
This prospective study was conducted between May 2016 and May 2019 in the intensive care unit (ICU) of Zhoupu Hospital, affiliated to Shanghai University of Medicine & Health Sciences. All patients diagnosed with sTBI (Glasgow Coma Scale [GCS] ≤8) and started on MV (Dräger Infinity C500, Dräger, Germany) were initially included. The patients whose hypoxemia (SpO2<90%) still could not be corrected through increasing the FiO2 more than 60% in combination with suction and intensive airway management were eventually enrolled in the study.
Exclusion criteria included: brain death, age below 18 or over 80 years, pregnancy, hemodynamic instability [heart rate >120 bpm or CPP (calculated by MAP-ICP) <60 mmHg], pneumothorax, pulmonary bulla, and acute myocardial infarction (elevated cardiac troponin T more than 3 times the normal upper limit accompanied by the ST-T change) etc. Approval for study conduct was granted by the clinical research ethics committee (no. ZPYYLL-2016-12), and written consent was obtained from all participants' next of kin.
Design and measurement
The treatment program was implemented referring to the Guidelines for the Management of sTBI [18]. All patients were in supine position at 30 degrees head of bed elevation and deeply sedated (0.05 mg/kg loading dose, followed by continuous intravenous infusion of midazolam 0.05–0.3 mg/kg/h and sufentanil 0.2 μg/kg/h) to maintain the Richmond Agitation-Sedation Scale (RASS) score of −5 and, thus, to remove the interference of cough and other neuronal and confounding factors on ICP. The ventilator settings remained consistent for each enrolled patient. The tidal volume was adjusted and maintained at 8 mL/kg of predicted body weight and the plateau pressure was maintained below 30 cmH2O. Support pressure was maintained at 12-14 cmH2O, initial PEEP was set at 3 cmH2O, and fraction of inspired oxygen (FiO2) was set at 35% - 50% to maintain pulse oxygen saturation (SpO2)>90%. The ICP was continuously monitored (Codman ICP ExpressTM, Johnson, USA) through an intraparenchimal transducers or ventricular catheter (Codman ICP Transducer, Johnson, USA) that was associated with a closed external ventricular drain if it existed during each measurement. Both central venous and arterial catheters were inserted to measure intra-arterial MAP and CVP. CPP was maintained more than 60-65mmHg. The static compliance of respiratory system (Cst) recorded from ventilator was indexed to the predicted body weight of the patients. During the study, the end-tidal carbon dioxide pressure (PetCO2) (monitoring by Drager Mainstream CO2 device, SN: ASHM-0552, Dräger, Germany) was maintained at 30-35 mmHg by adjusting tidal volume and respiratory rate, in order to avoid any effect of CO2 on ICP [19].
The stepwise increase of PEEP was set according to the method by Lim et al [20] when the hypoxemia persisted. Briefly, 100%-FiO2 was set up and PEEP was increased stepwise (from 3 cmH2O to 10 cmH2O, and to 15 cmH2O) every 2 min, which was a recruitment maneuver known as “extended sigh”. ICP, CVP, Cst, PetCO2, and CPP at the two levels of PEEP (3 cmH2O and 15 cmH2O) were measured respectively. After PEEP at 15 cmH2O maintained for 2 min, baseline ventilator setting was resumed.
Based on our research hypothesis and specific relationships between CVP and PEEP[16, 17], PICGap and other measurements (Cst, CPP, ICP, and PetCO2 ) were compared between two groups, and the prediction of ICP responsiveness to PEEP was tested by calculating the area under curves (AUC) of the receiver operating characteristic (ROC). Because there is no specified definition of the ICP responsiveness to PEEP adjustment, we stipulated that responder and non-responder referred as to an increment greater than or less than 20% of baseline ICP respectively when PEEP set up to 15 cmH2O.
During the research, remedied accordingly in case of: (1) CPP < 60 mmHg (norepinephrine 0.3–1.0 μg/kg/min was used); (2) ICP > 25 mmHg (PEEP was restored to 0); (3) increase in pressure plateau >35cmH2O (tidal volume was decreased and increase respiratory rate to maintain PetCO2 at 30–35mmHg); (4) SpO2 declined progressively (PEEP was restored to 0); and (5) suspicion of pneumothorax (PEEP was restored to 0, and chest radiography was undertaken). An equilibration period (≥90s) was entailed to ensure a normalized baseline PetCO2 through modulation of tidal volume and respiratory rate, which described by Flexman and colleagues [21].
Statistical analysis
Categorical variables are presented as numbers and percentages and were analyzed by Fisher’s exact test. Continuous covariates, including hemodynamic variables ICP, CVP, CPP, Cst, PetCO2 and CPP, were expressed as means ± standard errors. One-way analysis of variance (ANOVA) followed by the Bonferroni post hoc test was used for multiple comparisons. The predictive role of PICGap other related parameters recorded for ICP responsiveness to PEEP were tested by calculating the AUC of the ROC for ICP over the baseline value at the two levels of PEEP (3 and 15cmH2O). A p-value less than 0.05 was considered statistically significant. All statistical analyses were performed by using SPSS 20.0 for windows (IBM Co. NY, USA).