This study was conducted as an interventional trial in the surgical ICU of the University Hospital of Zurich between March 2013 and February 2016. The Cantonal Ethics Committee of Zurich approved and registered the study (KEK-ZH 2012–0542). Informed written consent was obtained from all participants or next of kin prior to study enrollment and/or from the patient after ICU discharge.
Patients in the TBI group were included in a study focusing on the effect of moderate hyperventilation on cerebral metabolism and thus selected according to previously published inclusion criteria [2]. Part of this trial was performed as preparation for the interventional trial in TBI patients (clinicaltrials.gov NCT03822026, retrospectively registered).
Patient population
The study was conducted in spontaneously breathing volunteers (Group 1), sedated and mechanically ventilated patients with presumed preserved CO2-CVR (Group 2), and sedated and mechanically ventilated patients suffering from severe TBI (TBI Group 3).
Inclusion criteria for Group 3 were adults (≥ 18 years of age) with non-penetrating head injury, with an initial Glasgow Coma Scale (GCS) score < 9 prior to sedation and intubation, extended neuromonitoring with ICP, brain tissue oxygenation (PbrO2), and/or microdialysis probes (TBI group), and also undergoing invasive mechanical ventilation with FIO2 < 60% and PEEP < 15 cmH2O. Exclusion criteria for all groups were decompressive craniectomy, pregnancy, pre-existing neurologic disease, previous TBI, acute cardiovascular disease, severe respiratory failure, acute or chronic liver disease, sepsis, and failure to obtain satisfactory bilateral TCCD signals. Patients with persisting hypovolemia or hemodynamic instability despite previous fluid resuscitation (defined as Global End-Diastolic Volume Index < 680 ml/m2, central venous oxygen saturation (ScvO2) < 60% and/or increase in mean arterial blood pressure (MAP) > 15% after passive leg raising test) were excluded.
The study was performed in the acute phase (12–36 h) after severe TBI (Group 3), while patients in Group 2 were investigated within 36 h after onset of mechanical ventilation.
All TBI patients were treated according to a cerebral perfusion orientated protocol aiming to achieve CPP > 70 mmHg, ICP ≤ 20 mmHg, PbrO2 > 15 mmHg, PaCO2 between 4.8 and 5.2 kPa. For Group 2, a MAP of 65 mmHg was targeted.
TCCD measurements
TCCD examination of the middle cerebral artery (MCA) was performed bilaterally via the transtemporal acoustic window by two experienced investigators (GB, SK), following standard techniques using a 5–1 MHz Probe (Philips CX 50, USA) [17]. Three repeated measurements of the peak systolic (PSV) and end-diastolic (EDV) velocity were performed for each side and an average value was calculated. The device also automatically calculated CBF-velocity (CBFV) and pulsatility index (PI).
Study protocol
In Group 1, ten spontaneously breathing volunteers were examined (Fig. 1, Panel A) using end-tidal carbon dioxide (EtCO2) to monitor ventilation. Subsequently, each volunteer was asked to gradually increase respiratory rate and tidal volume to achieve a reduction in EtCO2 of approximatively 5.5 mmHg. Once the desired ∆ETCO2 was achieved, the volunteer maintained a stable minute ventilation and EtCO2 for the duration of the TCCD measurements. After the TCCD measurements, the volunteer returned to resting ventilation.
Ten sedated and mechanically ventilated ICU patients in Group 2 and ten patients with severe TBI in Group 3 were investigated (Fig. 1, Panel B).
Under baseline conditions, a TCCD examination was performed and all variables were recorded (Fig. 1, point A). The minute ventilation was then increased over a 10-min period to obtain moderate HV by a stepwise increase in tidal volume and respiratory rate until a reduction of EtCO2 of 0.7 kPa (Fig. 1, point B) was achieved.
After 10 min of stable EtCO2, a second TCCD measurement was undertaken (begin of HV, Fig. 1, point C). The EtCO2 value was kept stable for 40 min, and then followed by a third TCCD examination (Fig. 1, point D). Finally, normoventilation was re-established over 10 min and all variables were allowed to return to baseline (Fig. 1, point E). A final TCCD examination was conducted at this time point. At each time point, MAP, SpO2 and EtCO2 were recorded.
Arterial blood gas tests (ABG) were obtained at points A, C, D and E, to monitor the changes in pH and PaCO2.
For study purpose, measurements and values obtained at timepoint A and B was used for group 1, while timepoint A and D was used for group 2 and 3.
Definition of cerebrovascular reactivity to carbon dioxide
CO2-CVR is expressed in terms of absolute and relative reactivity. Absolute CO2-CVR is defined as change in MFV (cm/s) per mmHg change in CO2. Relative CO2-CVR is defined as percentage change compared to baseline value.
$$\text{Absolute}\; \text{CO}_{2}-\text{CVR} = \Delta\text{MFV}/\Delta \text{CO}_{2}$$
$$\text{Relative}\; \text{CO}_{2}-\text{CVR} = ( \text{Absolute}\; \text{CO}_{2}-\text{CVR} / \text{baseline}\; \text{MFV}) \times 100$$
As the relative reactivity is less dependent on baseline values, it has been proposed as a more valuable indicator of CO2-CVR for analysis [10]. Relative reactivity was therefore chosen as the indicator for CO2-CVR.
∆MFV = difference in MFV between baseline and after HV.
∆CO2 = difference in CO2 between baseline and after HV. In Group 1, EtCO2 was used, while PaCO2 was used in Group 2 and TBI Group 3.
Hyperventilation constricts distal vessels, so a decrease in the absolute value of MFV is expected is the major intracranial vessels, as the ones investigated by TCCD.
Statistical analysis
Descriptive statistics were presented as mean with standard deviation (SD) or as median with interquartile range (IQR) for quantitative data. Categorical data were presented as absolute numbers with percentages. Comparisons of continuous variables among the three groups were performed with one-way analysis of variance or with the Kruskal–Wallis-test, as appropriate. For statistically significant p-values, post-hoc tests were performed, taking the multiple comparisons into account. Qualitative data among the three groups were compared with the Chi-Square test. In cases of statistically significant results, post-hoc comparisons were made with the appropriate critical level adjustment. Comparisons of quantitative data before and during hyperventilation were conducted with the paired Student’s t-test or with the Wilcoxon matched pairs test, as appropriate. All tests were done two-sided, and p-values < 0.05 were considered statistically significant. Stata version 12.1 (StatCorp. LP, College Station, TX, USA) was used for all statistical analysis.