Kinetics of the Cell Cycle Arrest Biomarkers (TIMP2 and IGFBP7) for the Diagnosis of Acute Kidney Injury in Critically Ill COVID-19 Patients.

BACKGROUND: Acute kidney injury (AKI) is highly prevalent in critical COVID-19 patients. The diagnosis and staging of AKI are based on serum creatinine (sCr) and urinary output criteria, with limitations in the functional markers. New cell-cycle arrest biomarkers [TIMP2]*[IGFBP7] have been proposed for early detection of AKI, but their role in critically ill COVID-19 patients is poorly understood. METHODS: We conducted an observational study to assess the performance of [TIMP2]*[IGFBP7] for the detection of AKI in critical COVID-19 patients admitted to our intensive care unit (ICU). We sampled urinary [TIMP2]*[IGFBP7] levels at ICU admission, 12 h, 24 h, and 48 h, and compared the results to the development of AKI, as well as baseline and laboratory data. RESULTS: Forty-one patients were enrolled. The median age was 66 years [57-72] and most were males (85%). Thirteen patients (31.7%) developed no/mild stage AKI, 19 patients (46.3%) moderate AKI, and nine patients (22.0%) severe AKI. The ICU mortality was 29.3%. sCr levels in the Emergency Department or at ICU admission were not significantly different according to AKI stage. [TIMP-2]*[IGFBP-7] urinary levels were elevated in severe AKI at 12 h after ICU admission, but not at ICU admission or 24 h or 48 h after ICU admission. CONCLUSION: Urinary biomarkers [TIMP-2]*[IGFBP-7] were generally increased in this population with a high prevalence of AKI, and were higher in patients with severe AKI measured at 12 h from ICU admission. Further studies are needed to evaluate the best timing of these biomarkers in this population.

Spinal anesthesia and hypotensive events in hip fracture surgical repair in elderly patients: a meta-analysis.

BACKGROUND: Spinal anesthesia (SA) is widely used for anesthetic management of patients undergoing hip surgery, and hypotension is the most common cardiovascular side effect of SA. This paper aims to assess the lowest effective dose of SA that reduces the occurrence of intraoperative hypotension in elderly patients scheduled for major lower limb orthopedic surgery. METHODS: We conducted a systematic review of randomized controlled trials (RCTs) performed in elderly patients scheduled for surgical hip repair and a meta-analysis with meta-regression on the occurrence of hypotensive episodes at different effective doses of anesthetics. We searched PUBMED®, EMBASE®, and the Cochrane Controlled Clinical trials registered. RESULTS: Our search retrieved 2085 titles, and after screening, 6 were finally included in both the qualitative and quantitative analysis, including 344 patients [15% (10-28) males], with a median (25th to 75th interquartile) age of 82 (80-85). The risk of bias assessment reported "low risk" for 5 (83.3%) and "some concerns" for 1 (16.7%) of the included RCTs. The low dose of SA of [mean 6.5 mg (1.9)] anesthetic was associated with a lower incidence of hypotension [OR = 0.09 (95%CI 0.04-0.21); p = 0.04; I2 = 56.9%], as compared to the high-dose of anesthetic [mean 10.5 mg (2.4)]. CONCLUSIONS: In the included studies of this meta-analysis, a mean dose of 6.5 mg of SA was effective in producing intraoperative comfort and motor block and associated with a lower incidence of hypotension as compared to a mean dose of 10.5 mg. TRIAL REGISTRATION: CRD42020193627.

Hemodynamic Instability during Acute Kidney Injury and Acute Renal Replacement Therapy: Pathophysiology and Clinical Implications.

Hemodynamic instability associated with acute renal replacement therapy (aRRT, HIRRT) and/or with acute kidney injury (AKI) is frequently observed in the intensive care unit; it affects patients' renal recovery, and negatively impacts short- and long-term mortality. A thorough understanding of mechanisms underlying HIRRT and AKI-related hemodynamic instability may allow the physician in adopting adequate strategies to prevent their occurrence and reduce their negative consequences. The aim of this review is to summarize the main alterations occurring in patients with AKI and/or requiring aRRT of those homeostatic mechanisms which regulate hemodynamics and oxygen delivery. In particular, a pathophysiological approach has been used to describe the maladaptive interactions between cardiac output and systemic vascular resistance occurring in these patients and leading to hemodynamic instability. Finally, the potential positive effects of aRRT on these pathophysiological mechanisms and on restoring hemodynamic stability have been described.

Near infrared spectroscopy as possible non-invasive monitor of slow vasogenic ICP waves.

We aimed to study synchronisation between ICP and near infrared spectroscopy (NIRS) variables induced by vasogenic waves of ICP during an infusion study in hydrocephalic patients and after TBI. Nineteen patients presenting with hydrocephalus underwent a diagnostic intraventricular constant-flow infusion test. The original concept of the methodology, presented in the current paper, was derived from this material. Then the method was applied in 40 TBI patients, with results reported in an observational manner. During monitoring, NIRS deoxygenated and oxygenated haemoglobin (Hb, HbO(2)) were recorded simultaneously with ICP. Moving correlation coefficient (6 min) between Hb and HbO(2) was tested as a marker of the slow vasogenic waves of ICP.During infusion studies ICP increased from 10.7 (5.1) mmHg to a plateau of 18.9 (7.6) mmHg, which was associated with an increase in the power of slow ICP waves (p = 0.000017). Fluctuations of Hb and HbO(2) at baseline negatively correlated with each other, but switched to high positive values during periods of increased ICP slow-wave activity during infusion (p < 0.001). Similar behaviour was observed in TBI patients: baseline negative Hb/HbO(2) correlation changed to positive values during peaks of ICP of vasogenic nature.Correlating changes in Hb and HbO(2) may be of use as a method of non-invasive detection of vasogenic ICP waves.

Changes in cerebral compartmental compliances during mild hypocapnia in patients with traumatic brain injury.

The benefit of induced hyperventilation for intracranial pressure (ICP) control after severe traumatic brain injury (TBI) is controversial. In this study, we investigated the impact of early and sustained hyperventilation on compliances of the cerebral arteries and of the cerebrospinal (CSF) compartment during mild hyperventilation in severe TBI patients. We included 27 severe TBI patients (mean 39.5 ± 3.4 years, 6 women) in whom an increase in ventilation (20% increase in respiratory minute volume) was performed during 50 min as part of a standard clinical CO(2) reactivity test. Using a new mathematical model, cerebral arterial compliance (Ca) and CSF compartment compliance (Ci) were calculated based on the analysis of ICP, arterial blood pressure, and cerebral blood flow velocity waveforms. Hyperventilation initially induced a reduction in ICP (17.5 ± 6.6 vs. 13.9 ± 6.2 mmHg; p < 0.001), which correlated with an increase in Ci (r(2) = 0.213; p = 0.015). Concomitantly, the reduction in cerebral blood flow velocities (CBFV, 74.6 ± 27.0 vs. 62.9 ± 22.9 cm/sec; p < 0.001) marginally correlated with the reduction in Ca (r(2) = 0.209; p = 0.017). During sustained hyperventilation, ICP increased (13.9 ± 6.2 vs. 15.3 ± 6.4 mmHg; p < 0.001), which correlated with a reduction in Ci (r(2) = 0.297; p = 0.003), but no significant changes in Ca were found during that period. The early reduction in Ca persisted irrespective of the duration of hyperventilation, which may contribute to the lack of clinical benefit of hyperventilation after TBI. Further studies are needed to determine whether monitoring of arterial and CSF compartment compliances may detect and prevent an adverse ischemic event during hyperventilation.

Effect of hyper- and hypocapnia on cerebral arterial compliance in normal subjects.

BACKGROUND: Changes in partial pressure of carbon dioxide (PaCO2) are associated with a decrease in cerebral blood flow (CBF) during hypocapnia and an increase in CBF during hypercapnia. However, the effects of changes in PaCO2 on cerebral arterial compliance (Ca) are unknown. METHODS: We assessed the changes in Ca in 20 normal subjects using monitoring of arterial blood pressure (ABP) and cerebral blood flow velocity (CBFV). Cerebral arterial blood volume (CaBV) was extracted from CBFV. Ca was defined as the ratio between the pulse amplitudes of CaBV (AMPCaBV ) and ABP (AMPABP). All parameters were recorded during normo-, hyper-, and hypocapnia. RESULTS: During hypocapnia, Ca was significantly lower than during normocapnia (.10±.04 vs. .17±.06; P<.001) secondary to a decrease in AMPCaBV (1.3±.4 vs. 1.9±.5; P<.001) and a concomitant increase in AMPABP (13.8±3.4 vs. 11.6±1.7 mmHg; P<.001). During hypercapnia, there was no change in Ca compared with normocapnia. Ca was inversely correlated with the cerebrovascular resistance during hypo- (R2=0.86; P<.001), and hypercapnia (R2=0.61; P<.001). CONCLUSION: Using a new mathematical model, we have described a reduction of Ca during hypocapnia. Further studies are needed to determine whether Ca may be an independent predictor of outcome in pathological conditions.

Noninvasive monitoring of cerebrovascular reactivity with near infrared spectroscopy in head-injured patients.

Monitoring of cerebrovascular pressure reactivity (PRx) has diagnostic and prognostic value in head-injured patients, but requires invasive monitoring of intracranial pressure (ICP). Near infrared spectroscopy (NIRS) is a noninvasive method that is suitable for continuous detection of cerebral blood volume changes. We compared a NIRS-based index of cerebrovascular reactivity, called total hemoglobin reactivity (THx), against standard measurements of PRx in a prospective observational study. Forty patients with closed-head injury were monitored daily with arterial blood pressure (ABP), ICP, and a NIRS-based total hemoglobin index. PRx and THx were calculated as the moving correlation coefficients using 5-min time windows between 10-sec averaged values of ICP and ABP, and total hemoglobin index and ABP, respectively. A total of 120 recordings were performed between the median first (IQR 0.75-2) and fourth (IQR 2-6) day after head injury, giving a total duration of 1760 hours. PRx and THx demonstrated a significant association across averaged individual recordings (r = 0.49, p < 0.0001), and across patients (r = 0.56, p = 0.0002). Assessment of optimal cerebral perfusion pressure (CPP) and ABP using THx was possible in about 50% of recordings, and showed a significant agreement with the optimal CPP and ABP assessed with PRx. THx may be of diagnostic value to optimize therapy oriented toward restoration and continuity of cerebrovascular reactivity, especially in patients for whom direct ICP monitoring is not feasible.

Slow vasogenic fluctuations of intracranial pressure and cerebral near infrared spectroscopy--an observational study.

BACKGROUND/PURPOSE: Increased slow-wave activity in intracranial pressure (ICP) signifies an exhausted cerebrospinal compensatory reserve across a range of conditions. In this study, we attempted to describe synchronisation between slow waves of ICP and of near-infrared spectroscopy (NIRS) variables during controlled elevation of ICP. METHOD: Nineteen patients presenting with symptomatic hydrocephalus underwent a Computerised Infusion Test. NIRS-derived indices, ICP and arterial blood pressure (ABP) were recorded simultaneously. FINDINGS: ICP increased from 9.3 (6.0) mmHg to a 17.1 (8.9) mmHg during infusion. Slow waves in ICP were accompanied by concurrent waves in each NIRS variable (including deoxygenated haemoglobin (Hb) and oxygenated haemoglobin (HbO2)) with a mean coherence of >0.7 and no significant phase shift. In the same bandwidth (0.3-1.8 min(-1)), ABP fluctuations occurred with a coherence of 0.77 and phase lead of 40° with respect to ICP. The power of ICP slow waves increased significantly during infusion plateau with a corresponding increase in power of Hb waves. CONCLUSIONS: Slow fluctuations in cerebral oximetry as detected by NIRS coincide with and are implicated in the origin of ICP slow waves and increases during periods of exhausted cerebrospinal compensatory reserve. NIRS may be used as a non-invasive marker of increased ICP slow waves (and therefore reduced CSF compensatory reserve).

Continuous assessment of cerebral autoregulation with near-infrared spectroscopy in adults after subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: In patients with subarachnoid hemorrhage, the assessment of cerebral autoregulation aids in prognosis as well as detection of vasospasm. Mx is a validated index of cerebral autoregulation based on measures of cerebral perfusion pressure and mean flow velocity on transcranial Doppler but is impractical for longer-term monitoring. Near-infrared spectroscopy is noninvasive and suitable for continuous monitoring of cerebral tissue oxygenation using the Tissue Oxygenation Index. In this study, we compared near-infrared spectroscopy-based indices of cerebral autoregulation (TOx) with Mx in patients with subarachnoid hemorrhage. METHODS: Arterial blood pressure, intracranial pressure, mean flow velocity, and Tissue Oxygenation Index were recorded. Mx and TOx were calculated as moving correlation coefficients between 10-second averaged values of cerebral perfusion pressure and mean flow velocity and between cerebral perfusion pressure and Tissue Oxygenation Index. We also calculated TOxA, the moving correlation coefficient between arterial blood pressure and Tissue Oxygenation Index. RESULTS: Fifty-one recording sessions were performed in 27 patients with subarachnoid hemorrhage with a total duration of 62.5 hours. Correlations of Mx and TOx over time varied markedly among individual recordings. However, time-averaging over the entire recording interval in each of the 51 recordings, we found correlations between Mx and TOx and between Mx and TOxA were highly significant. This correlation was even stronger after correction for multiple sampling for each patient, reaching r=0.81 for Mx and TOx and r=0.72 for Mx and TOxA. CONCLUSIONS: Near-infrared spectroscopy can be used to continuously assess cerebral autoregulation in adults after subarachnoid hemorrhage.

What shapes pulse amplitude of intracranial pressure?

The pulsatile component of intracranial pressure (ICP) has been shown to be a predictor of outcome in normal pressure hydrocephalus (NPH) and traumatic brain injury (TBI). Experimental studies have demonstrated that the pulse amplitude of ICP (AMP(ICP)) is dependent on the mean ICP (mICP), and on the pulse amplitude of the cerebral arterial blood volume (AMP(CaBV)), according to the exponential craniospinal compliance curve. In this study, we compared the influence of mICP and AMP(CaBV) on AMP(ICP) in patients with NPH (infusion study) and TBI (spontaneous recording). We retrospectively analyzed 25 NPH and 43 TBI patients with continuous monitoring of ICP and cerebral blood flow velocity (CBFV), as assessed with transcranial doppler. AMP(CaBV) was extracted from the CBFV waveform. The influence of mICP and AMP(CaBV) on AMP(ICP) were determined using partial coefficients a, b, and c of the multiple regression model: AMP(ICP) = a * mICP + b * AMP(CaBV) + c. AMP(ICP) was more dependent on mICP in NPH patients than in TBI patients (partial coefficient a = 0.93 versus -0.03; p < 0.001). On the contrary, AMP(ICP) was more dependent on AMP(CaBV) in patients with TBI than in those with NPH (b = 0.86 versus 0.10; p < 0.001). This study shows that AMP(ICP) depends mostly on changes in mean ICP during cerebrospinal fluid (CSF) infusion studies in patients with NPH, and on changes in cerebral arterial blood volume (AMP(CaBV)) in TBI patients. Further clinical studies will reveal whether AMP(ICP) is a better indicator of clinical severity and outcome than mICP in TBI and NPH patients.

A comparison study of cerebral autoregulation assessed with transcranial Doppler and cortical laser Doppler flowmetry.

OBJECTIVES: We compared autoregulation monitored with cortical laser Doppler flowmetry (LDF) and autoregulation monitored with transcranial Doppler (TCD) in the middle cerebral artery (MCA) to verify the hypothesis that, following brain trauma, cortical vessel autoregulation to intracranial hypertension is different than assessed in the MCA. METHODS: Data collected from 29 head injured patients were analysed retrospectively. Arterial blood pressure (ABP), intracranial pressure (ICP), flow velocity (FV) of the MCA and cortical flux (LDF) were monitored. Indices of cortical autoregulation (Lx) and autoregulation of cerebral blood flow in the MCA (Mx) were calculated as a moving correlation coefficient between slow waves of LDF and cerebral perfusion pressure (CPP) (Lx) or FV and CPP (Mx), respectively. Intact autoregulation was indicated by negative values for Lx and Mx; disturbed autoregulation was reflected by positive values. RESULTS: FV and LDF showed a high coherence in the slow wave spectrum of 1-4 cycles/min (mean: 0.79 +/- 0.12), indicating that similar information regarding autoregulation is carried by both signals. Mx and Lx correlated in all patients (R=0.43, p=0.02). On average, Lx was significantly higher than Mx; the mean difference was 0.13 +/- 0.38 (p=0.032), potentially due to severe intracranial hypertension above 40 mmHg, driving CPP values below 60 mmHg. CONCLUSION: After traumatic brain injury, cortical autoregulation appears to be worse than autoregulation assessed in the MCA during rising ICP and falling CPP. When CPP is above 60 mmHg, cortical assessed autoregulation is similar to autoregulation assessed in the MCA.

Plateau waves in head injured patients requiring neurocritical care.

OBJECT: Plateau waves often develop in neurointensive care patients. They are sudden increases in intracranial pressure (ICP) that lead to dramatic decreases of cerebral perfusion pressure (CPP) and can therefore contribute to ischemic secondary brain insult. The aim of this study was to analyze the occurrence of plateau waves in head injured patients requiring neurocritical care, their relation with cerebral autoregulation and impact on outcome. METHODS: Data were analyzed retrospectively in 444 head injured patients admitted to Neuroscience Critical Care Unit of Addenbrooke's Hospital in Cambridge, UK. Arterial blood pressure (ABP), intracranial pressure (ICP), heart rate (HR) were digitally recorded and derived indices calculated. Primary monitoring data, autoregulation indices, outcome of patients, initial CT findings (in a subgroup of patients), brain tissue monitoring data (in a subgroup) were compared between patients who developed plateau waves and those who did not. RESULTS: Plateau waves were observed in 109/444 patients (24.5%). They were significantly more frequent in younger patients. Impaired cerebrovascular pressure reactivity and depleted compensatory reserve were associated with vasodilatation on the top of the wave. Plateau waves were not associated with poorer outcome unless the episodes lasted for a long time (longer than 30-40 min). Plateau waves were more frequently seen in patients with lesser midline shift, lower volume of contusion on CT scan, absence of skull fractures, and lower brain tissue concentration of carbon dioxide. CONCLUSIONS: Plateau waves are frequent phenomenon. They are not associated with worse outcome unless they lead to sustained intracranial hypertension.

The monitoring of relative changes in compartmental compliances of brain.

The study aimed to develop a computational method for assessing relative changes in compartmental compliances within the brain: the arterial bed and the cerebrospinal space. The method utilizes the relationship between pulsatile components in the arterial blood volume, arterial blood pressure (ABP) and intracranial pressure (ICP). It was verified by using clinical recordings of intracranial pressure plateau waves, when massive vasodilatation accompanying plateau waves produces changes in brain compliances of the arterial bed (C(a)) and compliance of the cerebrospinal space (C(i)). Ten patients admitted after head injury with a median Glasgow Coma Score of 6 were studied retrospectively. ABP was directly monitored from the radial artery. Changes in the cerebral arterial blood volume were assessed using Transcranial Doppler (TCD) ultrasonography by digital integration of inflow blood velocity. During plateau waves, ICP increased (P = 0.001), CPP decreased (P = 0.001), ABP remained constant (P = 0.532), blood flow velocity decreased (P = 0.001). Calculated compliance of the arterial bed C(a) increased significantly (P = 0.001); compliance of the CSF space C(i) decreased (P = 0.001). We concluded that the method allows for continuous monitoring of relative changes in brain compartmental compliances. Plateau waves affect the balance between vascular and CSF compartments, which is reflected by the inverse change of compliance of the cerebral arterial bed and global compliance of the CSF space.