John Hauerberg

Laser Doppler flowmetry is valid for measurement of cerebral blood flow autoregulation lower limit in rats

Laser Doppler flowmetry (LDF) is a recent technique that is increasingly being used to monitor relative changes in cerebral blood flow whereas the intra‐arterial 133xenon injection technique is a well‐established method for repeated absolute measurements of cerebral blood flow. The aim of this study was to validate LDF for assessment of cerebral autoregulation and CO2 reactivity with the 133xenon injection technique as the gold standard. Simultaneous measurements of cerebral blood flow (CBF) were collected by LDF (CBFLDF) and the 133xenon method (CBFXe) while (1) cerebral autoregulation was challenged by controlled systemic haemorrhage, or (2) cerebral blood flow was varied by manipulating the arterial partial pressure of CO2 (Pa,CO2). LDF slightly overestimated CBF under conditions of haemorrhagic shock and haemodilution caused by controlled haemorrhage (paired t test, P < 0.05). However for pooled data, the autoregulation lower limit was similar when determined with the 133xenon and the LDF techniques: 65 ± 3.9 mmHg and 60 ± 5.6 mmHg, respectively. Linear regression analysis yielded CBFXe= (1.02 × CBFLDF) + 9.1 and r= 0.90. Even for substantial changes in Pa,CO2, the two methods resulted in similar results. We conclude that even though LDF overestimated CBF during haemorrhagic shock caused by controlled haemorrhage, the lower limit autoregulation was correctly identified. The laser Doppler technique provides a reliable method for detection of a wide range of cerebral blood flow changes under CO2 challenge. Haemodilution influences the two methods differently causing relative overestimation of blood flow by the laser Doppler technique compared to the 133xenon method.

Cerebral Blood Flow Autoregulation in Acute Intracranial Hypertension

The present series of experiments was carried out to investigate CBF autoregulation during fixed levels of acute increased intracranial pressure (ICP). Three groups of six rats each, one with normal ICP (8 mm Hg), one with moderately increased ICP (30 mm Hg), and one with severely increased ICP (50 mm Hg), were investigated. ICP was maintained by continuous infusion of lactated Ringer solution into the cisterna magna. Cerebral perfusion pressure (CPP), calculated as mean arterial blood pressure – ICP, was increased by intravenously infused norepinephrine and decreased by controlled bleeding. In all groups the corresponding autoregulation curve included a plateau where CBF was independent of changes in CPP, demonstrating intact autoregulation. However, a significant shift of the lower limit of autoregulation (LL) toward lower CPP levels during severe intracranial hypertension was observed (p < 0.006). In the controls the LL was found at CPP = 73 ±6 mm Hg, in moderately increased ICP the LL was 59 ± 4 mm Hg, and in severely increased ICP the LL was 51 ±4 mm Hg. These results indicate that an acute elevation of ICP activates a reserve capacity of cerebral resistance vessels that dilate further below the normal physiological LL to maintain CBF at low levels of CPP.

Brain hypoxanthine concentration correlates to lactate/pyruvate ratio but not intracranial pressure in patients with acute liver failure

BACKGROUND & AIMS The pathogenesis of cerebral edema in acute liver failure is suggested, in in vitro and animal studies, to involve a compromised oxidative metabolism with a decrease in cerebral ATP levels and an increase in purine concentrations. In this study we hypothesize that the cerebral concentrations of hypoxanthine, inosine, and lactate/pyruvate (LP) ratio are increased and correlated in patients with acute liver failure. Furthermore, we expect the purines and L/P ratio to correlate with intracranial pressure (ICP) (positively), and cerebral perfusion pressure (CPP) (negatively). METHODS In 17 patients (aged 18-60 years) with acute liver failure and severe hyperammonemia (182 ± 36 μM (mean ± SD)), cerebral microdialysis was performed, and ICP and CPP were monitored. Microdialysate concentrations of hypoxanthine, inosine, lactate, and pyruvate were measured. RESULTS The hypoxanthine concentration was 23.0 ± 12 μM in early samples and 11.7 ± 6.8 μM in late samples (normal level ~2.0 μM). The inosine concentration was 7.2 ± 7.1 μM and 2.8 ± 1.6 μM, and the LP ratio was 55.8 ± 21.6 and 45.6 ± 20.8, respectively (normal level ~18). Hypoxanthine correlated significantly to LP ratio (r(2)=0.40, p<0.01) while inosine did not. The purine levels and L/P ratio did not correlate to ICP or CPP, nor did they differ between patients with high ICP (>20 mmHg, n=9) and patients without (n=8). CONCLUSIONS This study shows that the high cerebral LP ratio correlates to the hypoxanthine level in patients with acute liver failure. However, these metabolic alterations were not related to the development of intracranial hypertension.

A multicentre randomized controlled trial of moderate hypothermia to prevent intracranial hypertension in acute liver failure

BACKGROUND & AIMS Animal models and human case series of acute liver failure (ALF) suggest moderate hypothermia (MH) to have protective effects against cerebral oedema (CO) development and intracranial hypertension (ICH). However, the optimum temperature for patient management is unknown. In a prospective randomized controlled trial we investigated if maintenance of MH prevented development of ICH in ALF patients at high risk of the complication. METHODS Patients with ALF, high-grade encephalopathy and intracranial pressure (ICP) monitoring in specialist intensive care units were randomized by sealed envelope to targeted temperature management (TTM) groups of 34°C (MH) or 36°C (control) for a period of 72h. Investigators were not blinded to group assignment. The primary outcome was a sustained elevation in ICP >25mmHg, with secondary outcomes the occurrence of predefined serious adverse effects, magnitude of ICP elevations and cerebral and all-cause hospital mortality (with or without transplantation). RESULTS Forty-six patients were randomized, of whom forty-three were studied. There was no significant difference between the TTM groups in the primary outcome during the study period (35% vs. 27%, p=0.56), for the MH (n=17) or control (n=26) groups respectively, relative risk 1.31 (95% CI 0.53-3.2). Groups had similar incidence of adverse events and overall mortality (41% vs. 46%, p=0.75). CONCLUSIONS In patients with ALF at high risk of ICH, MH at 33-34°C did not confer a benefit above management at 36°C in prevention of ICH or in overall survival. This study did not confirm advantage of its prophylactic use. (ISRCTN registration number 74268282; no funding.) LAY SUMMARY Studies in animals with acute liver failure (ALF) have suggested that cooling (hypothermia) could prevent or limit the development of brain swelling, a dangerous complication of the condition. There is limited data on its effects in humans. In a randomized controlled trial in severely ill patients with ALF we compared the effects of different temperatures and found no benefit on improving survival or preventing brain swelling by controlling temperature at 33-34°C against 36°C.

56 THE PROPHYLACTIVE EFFECT OF MILD HYPOTHERMIA TO PREVENT BRAIN EDEMA IN PATIENTS WITH ACUTE LIVER FAILURE: RESULTS OF A MULTICENTER RANDOMIZED, CONTROLLED TRIAL

56 THE PROPHYLACTIVE EFFECT OF MILD HYPOTHERMIA TO PREVENT BRAIN EDEMA IN PATIENTS WITH ACUTE LIVER FAILURE: RESULTS OF A MULTICENTER, RANDOMIZED, CONTROLLED TRIAL F.S. Larsen, N. Murphy, W. Bernal, P.N. Bjerring, J. Hauerberg, J. Wendon, EUROALF Group. Hepatology, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark; Intensive Care, Queen Elizabeth Hospital, Birmingham, Institute of Liver Studies, London, UK; Neurosurgy, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark; Institute of Liver Studies, Kings College Hospital, London, UK E-mail: stolze@post3.tele.dk

Effects of graded hyperventilation on cerebral blood flow autoregulation in experimental subarachnoid hemorrhage.

An impaired CBF autoregulation can be restored by hyperventilation at a PaCO2 level of about 2.9 to 4.1 kPa (22 to 31 mm Hg). However, it is uncertain whether the restoring effect can take place at lesser degrees of hypocapnia. In the current study, CBF autoregulation was studied at four PaCO2 levels: 5.33 kPa (40 mm Hg, normoventilation), 4.67 kPa (35 mm Hg, slight hyperventilation), 4.00 kPa (30 mm Hg, moderate hyperventilation), and 3.33 kPa (25 mm Hg, profound hyperventilation). At each PaCO2 level, eight rats 2 days after experimental subarachnoid hemorrhage (SAH) and eight shamoperated controls were studied. The CBF was measured by the intracarotid 133Xe method. The CBF autoregulation was found to be intact in all controls but completely disturbed in the normoventilated SAH rats. However, by slight hyperventilation, CBF autoregulation was restored in seven of eight SAH rats with a decline in CBF of 10%. The CBF autoregulation was found intact in all of the moderately or profoundly hyperventilated SAH rats, whereas the decline in CBF was 21% and 28%, respectively. In conclusion, hyperventilation to a PaCO2 level between 4.00 and 4.67 kPa (30 to 35 mm Hg) appears to be sufficient for reestablishing an impaired autoregulation after SAH.

The upper limit of cerebral blood flow autoregulation in acute intracranial hypertension.

The present series of experiments was performed to investigate the influence of acute intracranial hypertension on the upper limit (UL) of cerebral blood flow (CBF) autoregulation. Three groups of eight rats each—one with normal intracranial pressure (ICP) (2 mmHg), one with ICP = 30 mmHg, and one with ICP = 50 mmHg— were investigated. Intracranial hypertension was maintained by continuous infusion of lactated Ringers solution into the cisterna magna, where the pressure was used as ICP. Cerebral perfusion pressure (CPP), calculated as mean arterial blood pressure (MABP) - ICP, was increased stepwise by continuous intravenous infusion of norepinephrine. CBF was calculated by the intracarotid 133Xe method. In all three groups the corresponding CBF/CPP curve included a plateau where CBF was independent of changes in CPP, showing intact autoregulation. At normal ICP the UL was found at a CPP of 141 ± 2 mmHg, at ICP = 30 mmHg the UL was 103 ± 5 mmHg, and at ICP = 50 mmHg the UL was found at 88 ± 7 mmHg. This shift of the UL was more pronounced than the shift of the lower limit (LL) of the CBF autoregulation found previously. We conclude that intracranial hypertension is followed by both a shift toward lower CPP values and a narrowing of the autoregulated interval between the LL and the UL.

Spreading depolarizations in patients with spontaneous intracerebral hemorrhage: Association with perihematomal edema progression.

Pathophysiologic mechanisms of secondary brain injury after intracerebral hemorrhage and in particular mechanisms of perihematomal-edema progression remain incompletely understood. Recently, the role of spreading depolarizations in secondary brain injury was established in ischemic stroke, subarachnoid hemorrhage and traumatic brain injury patients. Its role in intracerebral hemorrhage patients and in particular the association with perihematomal-edema is not known. A total of 27 comatose intracerebral hemorrhage patients in whom hematoma evacuation and subdural electrocorticography was performed were studied prospectively. Hematoma evacuation and subdural strip electrode placement was performed within the first 24 h in 18 patients (67%). Electrocorticography recordings started 3 h after surgery (IQR, 3–5 h) and lasted 157 h (median) per patient and 4876 h in all 27 patients. In 18 patients (67%), a total of 650 spreading depolarizations were observed. Spreading depolarizations were more common in the initial days with a peak incidence on day 2. Median electrocorticography depression time was longer than previously reported (14.7 min, IQR, 9–22 min). Postoperative perihematomal-edema progression (85% of patients) was significantly associated with occurrence of isolated and clustered spreading depolarizations. Monitoring of spreading depolarizations may help to better understand pathophysiologic mechanisms of secondary insults after intracerebral hemorrhage. Whether they may serve as target in the treatment of intracerebral hemorrhage deserves further research.

Effects of morphine on cerebral blood flow autoregulation CO2-reactivity in experimental subarachnoid hemorrhage.

Previous reports show that naloxone improves ischemic deficits and clinical conditions in patients after subarachnoid hemorrhage (SAH). These observations have raised concern about the routine use of morphine in the treatment of severe headache after SAH. The present study was carried out to investigate the effects of morphine on cerebral vasoreactivity after experimental SAH. Cerebral blood flow (CBF) autoregulation was studied in two groups of eight rats each with experimental SAH. A bolus intravenous injection of morphine, 1 mg/kg, was administered in one group and the other was used as a control group. During eucapnia, CBF was measured by the intracarotid 133Xenon method during decreasing mean arterial blood pressure (MABP). CO2-reactivity was investigated in two corresponding groups where CBF was measured at decreasing PaCO2 levels during constant MABP. Morphine decreased mean baseline CBF by 34% and 26% in the study of autoregulation and CO2-reactivity, respectively. Cerebral blood flow autoregulation was found impaired in both controls and the morphine group. However, the mean slope of the linear regression lines of CBF/MABP was 0.49 +/- 0.32 ml/100g/min/mm Hg in the morphine group, which was significantly lower than 1.24 +/- 0.59 ml/100g/min/mm Hg in the controls (p < 0.05). Also the mean CO2-reactivity was significantly lower, 0.64 +/- 0.53 %/0.1kPa, in the morphine group, compared to 2.36 +/- 0.87 %/0.1kPa in the controls (p < 0.001). The results show that in rats with SAH, morphine partially restores CBF autoregulation but attenuates CO2-reactivity.

Effects of alterations in arterial CO2 tension on cerebral blood flow during acute intracranial hypertension in rats.

Cerebrovascular reactivity to CO2 in clinical and experimental studies has been found to be impaired during increased intracranial pressure (ICP). However, from previous study results it has not been possible to estimate whether the impairment was caused by elevated ICP, or caused by decreased cerebral perfusion pressure (CPP). The current study was carried out in a group of unmanipulated control rats and in six investigation groups of six rats each: two groups with elevated ICP (30 and 50 mm Hg) and spontaneous arterial blood pressure (MABP), two groups with spontaneous ICP and arterial hypotension (77 and 64 mm Hg), and two groups with elevated ICP (30 and 50 mm Hg) and arterial hypertension (124 mm Hg). Intracranial hypertension was induced by continuous infusion of lactated Ringers solution into the cisterna magna, arterial hypotension by controlled bleeding, and arterial hypertension by continuous administration of norepinephrine intravenously. Cerebral blood flow (CBF) was measured repetitively by the intraarterial 133Xe method at different levels of arterial PCO2. In each individual animal, CO2 reactivity was calculated from an exponential regression line obtained from the corresponding CBF/PaCO2 values. By plotting each individual value of CO2 reactivity against the corresponding CPP value from the seven investigation groups, CPP was significantly and directly related to CO2 reactivity of CBF (P < .001). No correlation was found by plotting CO2 reactivity values against the corresponding MABP values or the corresponding ICP values. Thus, the results show that CO2 reactivity is at least partially determined by CPP and that the impaired CO2 reactivity observed at intracranial hypertension and arterial hypotension may be caused by reduced CPP.