Rogier V. Immink

Impaired Cerebral Autoregulation in Patients With Malignant Hypertension

Background—In patients with a malignant hypertension, immediate parenteral treatment with blood pressure–lowering agents such as intravenous sodium nitroprusside (SNP) is indicated. In this study, we evaluated static and dynamic cerebral autoregulation (CA) during acute blood pressure lowering with SNP in these patients. Methods and Results—In 8 patients with mean arterial pressure (MAP) >140 mm Hg and grade III or IV hypertensive retinopathy at hospital admission, middle cerebral artery blood velocity (MCA V) and blood pressure were monitored. Dynamic CA was expressed as the 0.1-Hz MCA Vmean to MAP phase lead and static CA as the MCA Vmean to MAP relationship during SNP treatment. Eight normotensive subjects served as a reference group. In the patients, the MCA Vmean to MAP phase lead was lower (30±8° versus 58±5°, mean±SEM; P<0.05), whereas the transfer gain tended to be higher. During SNP treatment, target MAP was reached within 90 minutes in all patients. The MCA Vmean decrease was 22±4%, along with a 27±3% reduction in MAP (from 166±4 to 121±6 mm Hg; P<0.05) in a linear fashion (averaged slope, 0.82±0.15% cm · s−1 · % mm Hg−1; r=0.70±0.07). Conclusions—In patients with malignant hypertension, dynamic CA is impaired. An MCA Vmean plateau was not detected during the whole SNP treatment, indicating loss of static CA as well. This study showed that during the whole rapid reduction in blood pressure with SNP, MCA Vmean decreases almost one on one with MAP.

Dynamic cerebral autoregulatory capacity is affected early in Type 2 diabetes

Type 2 diabetes is associated with an increased risk of endothelial dysfunction and microvascular complications with impaired autoregulation of tissue perfusion. Both microvascular disease and cardiovascular autonomic neuropathy may affect cerebral autoregulation. In the present study, we tested the hypothesis that, in the absence of cardiovascular autonomic neuropathy, cerebral autoregulation is impaired in subjects with DM+ (Type 2 diabetes with microvascular complications) but intact in subjects with DM- (Type 2 diabetes without microvascular complications). Dynamic cerebral autoregulation and the steady-state cerebrovascular response to postural change were studied in subjects with DM+ and DM-, in the absence of cardiovascular autonomic neuropathy, and in CTRL (healthy control) subjects. The relationship between spontaneous changes in MCA V(mean) (middle cerebral artery mean blood velocity) and MAP (mean arterial pressure) was evaluated using frequency domain analysis. In the low-frequency region (0.07-0.15 Hz), the phase lead of the MAP-to-MCA V(mean) transfer function was 52+/-10 degrees in CTRL subjects, reduced in subjects with DM- (40+/-6 degrees ; P<0.01 compared with CTRL subjects) and impaired in subjects with DM+ (30+/-5 degrees ; P<0.01 compared with subjects with DM-), indicating less dampening of blood pressure oscillations by affected dynamic cerebral autoregulation. The steady-state response of MCA V(mean) to postural change was comparable for all groups (-12+/-6% in CTRL subjects, -15+/-6% in subjects with DM- and -15+/-7% in subjects with DM+). HbA(1c) (glycated haemoglobin) and the duration of diabetes, but not blood pressure, were determinants of transfer function phase. In conclusion, dysfunction of dynamic cerebral autoregulation in subjects with Type 2 diabetes appears to be an early manifestation of microvascular disease prior to the clinical expression of diabetic nephropathy, retinopathy or cardiovascular autonomic neuropathy.

Transient influence of end-tidal carbon dioxide tension on the postural restraint in cerebral perfusion

In the upright position, cerebral blood flow is reduced, maybe because arterial carbon dioxide partial pressure (Pa(CO(2))) decreases. We evaluated the time-dependent influence of a reduction in Pa(CO(2)), as indicated by the end-tidal Pco(2) tension (Pet(CO(2))), on cerebral perfusion during head-up tilt. Mean arterial pressure, cardiac output, middle cerebral artery mean flow velocity (MCA V(mean)), and dynamic cerebral autoregulation at supine rest and 70 degrees head-up tilt were determined during free breathing and with Pet(CO(2)) clamped to the supine level. The postural changes in central hemodynamic variables were equivalent, and the cerebrovascular autoregulatory capacity was not significantly affected by tilt or by clamping Pet(CO(2)). In the first minute of tilt, the decline in MCA V(mean) (10 +/- 4 vs. 3 +/- 4 cm/s; mean +/- SE; P < 0.05) and Pet(CO(2)) (6.8 +/- 4.3 vs. 1.7 +/- 1.6 Torr; P < 0.05) was larger during spontaneous breathing than during isocapnic tilt. However, after 2 min in the head-up position, the reduction in MCA V(mean) was similar (7 +/- 5 vs. 6 +/- 3 cm/s), although the spontaneous decline in Pet(CO(2)) was maintained (P < 0.05 vs. isocapnic tilt). These results suggest that the potential contribution of Pa(CO(2)) to the postural reduction in MCA V(mean) is transient, leaving the mechanisms for the sustained restrain in MCA V(mean) to be identified.

Hyperventilation, Cerebral Perfusion and Syncope

This review summarizes evidence in humans for an association between hyperventilation (HV)-induced hypocapnia and a reduction in cerebral perfusion leading to syncope defined as transient loss of consciousness (TLOC). The cerebral vasculature is sensitive to changes in both the arterial carbon dioxide (PaCO2) and oxygen (PaO2) partial pressures so that hypercapnia/hypoxia increases and hypocapnia/hyperoxia reduces global cerebral blood flow. Cerebral hypoperfusion and TLOC have been associated with hypocapnia related to HV. Notwithstanding pronounced cerebrovascular effects of PaCO2 the contribution of a low PaCO2 to the early postural reduction in middle cerebral artery blood velocity is transient. HV together with postural stress does not reduce cerebral perfusion to such an extent that TLOC develops. However when HV is combined with cardiovascular stressors like cold immersion or reduced cardiac output brain perfusion becomes jeopardized. Whether, in patients with cardiovascular disease and/or defect, cerebral blood flow cerebral control HV-induced hypocapnia elicits cerebral hypoperfusion, leading to TLOC, remains to be established.

Cerebral Hemodynamics During Treatment With Sodium Nitroprusside Versus Labetalol in Malignant Hypertension

In patients with malignant hypertension, immediate blood pressure reduction is indicated to prevent further organ damage. Because cerebral autoregulatory capacity is impaired in these patients, a pharmacologically induced decline of blood pressure reduces cerebral blood flow with the danger of cerebral hypoperfusion. We compared the reduction in transcranial Doppler–determined middle cerebral artery blood velocity during blood pressure lowering with sodium nitroprusside with that of labetalol. Therefore, in 15 patients, fulfilling World Health Organization criteria for malignant hypertension, beat-to-beat mean arterial pressure, systemic vascular resistance (Modelflow), mean middle cerebral artery blood velocity, and cerebrovascular resistance index (mean blood pressure:mean middle cerebral artery blood flow velocity ratio), were monitored during treatment with sodium nitroprusside (n=8) or labetalol (n=7). The reduction in mean arterial blood pressure with sodium nitroprusside (−28±3%; mean±SEM) and labetalol (−28±4%) was comparable. With labetalol, both systemic and cerebral vascular resistance decreased proportionally (−13±10% and −17±5%), whereas with sodium nitroprusside, the decline in systemic vascular resistance was larger than that in cerebral vascular resistance (−53±4% and −7±4%). The rate of reduction in middle cerebral artery blood velocity was smaller with labetalol than with sodium nitroprusside (0.45±0.05% versus 0.78±0.04% cm · s−1 · %mm Hg−1; P<0.05). In conclusion, sodium nitroprusside reduced systemic vascular resistance rather than cerebral vascular resistance with a larger rate of reduction in middle cerebral artery blood velocity, suggesting a preferential blood flow to the low resistance systemic vascular bed rather than the cerebral vascular bed.

Effects of aging on the cerebrovascular orthostatic response

When healthy subjects stand up, it is associated with a reduction in cerebral blood velocity and oxygenation although cerebral autoregulation would be considered to prevent a decrease in cerebral perfusion. Aging is associated with a higher incidence of falls, and in the elderly falls may occur particularly during the adaptation to postural change. This study evaluated the cerebrovascular adaptation to postural change in 15 healthy younger (YNG) vs. 15 older (OLD) subjects by recordings of the near-infrared spectroscopy-determined cerebral oxygenation (cO₂Hb) and the transcranial Doppler-determined mean middle cerebral artery blood velocity (MCA V(mean)). In OLD (59 (52-65) years) vs. YNG (29 (27-33) years), the initial postural decline in mean arterial pressure (-52 ± 3% vs. -67 ± 3%), cO₂Hb (-3.4 ± 2.5 μmoll(-1) vs. -5.3 ± 1.7 μmoll(-1)) and MCA V(mean) (-16 ± 4% vs. -29 ± 3%) was smaller. The decline in MCA V(mean) was related to the reduction in MAP. During prolonged orthostatic stress, the decline in MCA V(mean)and cO(2)Hb in OLD remained smaller. We conclude that with healthy aging the postural reduction in cerebral perfusion becomes less prominent.

Central Versus Peripheral Blood Pressure in Malignant Hypertension; Effects of Antihypertensive Treatment

BACKGROUND Sodium nitroprusside (SNP) and labetalol are recommended for the immediate treatment of malignant hypertension. Both are intravenous agents but have different effects on systemic hemodynamics, and may have differential effects on pulse-wave reflection and pulse-pressure amplification, with consequences for peripheral versus central blood pressures (BPs). METHODS We conducted a nonrandomized, open-label study of 8 patients treated with sodium nitroprusside (mean age (±SD), 44±14 years; 6 males; diastolic/systolic BP, 225±22/135±8mm Hg) and 6 patients treated with intravenous labetalol (mean age, 39±15 years; 4 males; systolic/diastolic BP, 232±22/138±17mm Hg) before and after treatment for malignant hypertension, aiming at a 25% reduction in mean arterial pressure. We measured peripheral pressures with an intra-arterial catheter in the radial artery and derived central pressures with a generalized transfer filter. RESULTS Mean arterial pressure was similarly reduced with sodium nitroprusside and labetalol (by 27% and 30%, respectively; P = 0.76). There was a nonsignificantly greater reduction in peripheral systolic blood pressure (SBP) with labetalol than with sodium nitroprusside (29±11% vs. 18±7%, P = 0.08). The decline in peripheral diastolic blood pressure (DBP) with the two agents was comparable, whereas the reduction in peripheral pulse pressure was 8±16% with SNP and 33±17% with labetalol (P = 0.01). The decline in reflection magnitude was greater with SNP than with labetalol. There were no significant differences in the reduction of central BP with SNP and labetalol. The amplification of PP increased with SNP but did not change with labetalol. CONCLUSIONS We found no difference in central SBP or PP in subjects treated with SNP and labetalol, but labetalol produced a greater reduction in peripheral SBP and PP in the immediate treatment of malignant hypertension.

The Cerebrovascular Pressure-Flow Relationship: A Simple Concept But a Complex Phenomenon

To the Editor: We read with interest the article by Lucas et al1 on mean middle cerebral artery blood velocity (MCA V mean) and cerebral tissue oxygenation during changes in blood pressure. We may question whether the conclusion by the authors, “that cerebral blood flow (CBF) and oxygenation are not independent of changes in blood pressure requires a paradigm shift in the concept of cerebral autoregulation,” is new or even indisputably supported by the data provided. The authors’ proposed new paradigm shift was highlighted in 1983 by Heistad and Kontos2 stating that CBF is not …

Cerebral oxygenation during changes in vascular resistance and flow in patients on cardiopulmonary bypass - a physiological proof of concept study.

Despite a rise in blood pressure, cerebral oxygenation decreases following phenylephrine administration, and we hypothesised that phenylephrine reduces cerebral oxygenation by activating cerebral α1 receptors. We studied patients on cardiopulmonary bypass during constant flow. Phenylephrine raised mean arterial pressure (α1‐mediated) from mean (SD) 69 (8) mmHg to 79 (8) mmHg; p = 0.001, and vasopressin raised mean arterial pressure (V1 mediated) from 69 (8) mmHg to 83 (6) mmHg; p = 0.001. Both drugs elicited a comparable decrease in cerebral oxygenation from 61 (7)% to 60 (7)%; p = 0.023 and 61 (8)% to 59 (8)%; p = 0.022, respectively. This implies that after phenylephrine or vasopressin administration, cerebral oxygenation declines as a result of cerebral vasoconstriction, due to either both cerebral α1 and V1 receptors being equipotentially activated or to an intrinsic myogenic mechanism of cerebral vasculature in reaction to blood pressure elevation.

Sevoflurane based anaesthesia does not affect already impaired cerebral autoregulation in patients with type 2 diabetes mellitus

Background: The baroreflex regulates arterial blood pressure (BP). During periods when blood pressure changes, cerebral blood flow (CBF) is kept constant by cerebral autoregulation (CA). In patients with diabetes mellitus (DM), low baroreflex sensitivity (BRS) is associated with impaired CA. As sevoflurane‐based anaesthesia obliterates BRS, we hypothesised that this could aggravate the already impaired CA in patients with DM resulting in a ‘double‐hit’ on cerebral perfusion leading to increased fluctuations in blood pressure and cerebral perfusion. Methods: On the day before surgery, we measured CBF velocity (CBFV), heart rate, and BP to determine BRS and CA efficacy (CBFVmean‐to‐BPmean‐phase lead) in 25 patients with DM and in 14 controls. During the operation, BRS and CA efficacy were determined during sevoflurane‐based anaesthesia. Patients with DM were divided into a group with high BRS (DMBRS↑) and a group with low BRS (DMBRS↓). Values presented are median (inter‐quartile range). Results: Preoperative vs intraoperative BRS was 6.2 (4.5–8.5) vs 1.9 (1.1–2.5, P<0.001) ms mm Hg−1 for controls, 5.8 (4.9–7.6) vs 2.7 (1.5–3.9, P<0.001) ms mm Hg−1 for patients with DMBRS↑, and 1.9 (1.5–2.8) vs 1.1 (0.6–2.5, P=0.31) ms mm Hg−1 for patients with DMBRS↓. Preoperative vs intraoperative CA efficacy was 43° (38–46) vs 43° (38–51, P=0.30), 44° (36–49) vs 41° (32–49, P=0.52), and 34° (28–40) vs 30° (27–38, P=0.64) for controls, DMBRS↑, and DMBRS↓ patients, respectively. Conclusions: In diabetic patients with low preoperative BRS, preoperative CA efficacy was also impaired. In controls and diabetic patients, CA was unaffected by sevoflurane‐based anaesthesia. We therefore conclude that sevoflurane‐based anaesthesia does not contribute to a ‘double‐hit’ phenomenon on cerebral perfusion. Clinical trial registration: NCT 03071432.