Heparin resistance in COVID-19 patients in the intensive care unit.

Patients with COVID-19 have a coagulopathy and high thrombotic risk. In a cohort of 69 intensive care unit (ICU) patients we investigated for evidence of heparin resistance in those that have received therapeutic anticoagulation. 15 of the patients have received therapeutic anticoagulation with either unfractionated heparin (UFH) or low molecular weight heparin (LMWH), of which full information was available on 14 patients. Heparin resistance to UFH was documented in 8/10 (80%) patients and sub-optimal peak anti-Xa following therapeutic LMWH in 5/5 (100%) patients where this was measured (some patients received both anticoagulants sequentially). Spiking plasma from 12 COVID-19 ICU patient samples demonstrated decreased in-vitro recovery of anti-Xa compared to normal pooled plasma. In conclusion, we have found evidence of heparin resistance in critically unwell COVID-19 patients. Further studies investigating this are required to determine the optimal thromboprophylaxis in COVID-19 and management of thrombotic episodes.

Correction to: Heparin resistance in COVID­19 patients in the intensive care unit.

In the original publication of this article, one of the co-author name "D. de Monteverde-Robb" was inadvertently mentioned as "R. de Monteverde-Robb". The correct author name is "D. de Monteverde-Robb". This error has been corrected with this erratum.

Targeted temperature management in patients with intracerebral haemorrhage, subarachnoid haemorrhage, or acute ischaemic stroke: consensus recommendations.

BACKGROUND: A modified Delphi approach was used to identify a consensus on practical recommendations for the use of non-pharmacological targeted temperature management in patients with intracerebral haemorrhage, subarachnoid haemorrhage, or acute ischaemic stroke with non-infectious fever (assumed neurogenic fever). METHODS: Nine experts in the management of neurogenic fever participated in the process, involving the completion of online questionnaires, face-to-face discussions, and summary reviews, to consolidate a consensus on targeted temperature management. RESULTS: The panel's recommendations are based on a balance of existing evidence and practical considerations. With this in mind, they highlight the importance of managing neurogenic fever using a single protocol for targeted temperature management. Targeted temperature management should be initiated if the patient temperature increases above 37.5°C, once an appropriate workup for infection has been undertaken. This helps prevent prophylactic targeted temperature management use and ensures infection is addressed appropriately. When neurogenic fever is detected, targeted temperature management should be initiated rapidly if antipyretic agents fail to control the temperature within 1 h, and should then be maintained for as long as there is potential for secondary brain damage. The recommended target temperature for targeted temperature management is 36.5-37.5°C. The use of advanced targeted temperature management methods that enable continuous, or near continuous, temperature measurement and precise temperature control is recommended. CONCLUSIONS: Given the limited heterogeneous evidence currently available on targeted temperature management use in patients with neurogenic fever and intracerebral haemorrhage, subarachnoid haemorrhage, or acute ischaemic stroke, a Delphi approach was appropriate to gather an expert consensus. To aid in the development of future investigations, the panel provides recommendations for data gathering.

Pulsatile intracranial pressure and cerebral autoregulation after traumatic brain injury.

BACKGROUND: Strong correlation between mean intracranial pressure (ICP) and its pulse wave amplitude (AMP) has been demonstrated in different clinical scenarios. We investigated the relationship between invasive mean arterial blood pressure (ABP) and AMP to explore its potential role as a descriptor of cerebrovascular pressure reactivity after traumatic brain injury (TBI). METHODS: We retrospectively analyzed data of patients suffering from TBI with brain monitoring. Transcranial Doppler blood flow velocity, ABP, ICP were recorded digitally. Cerebral perfusion pressure (CPP) and AMP were derived. A new index-pressure-amplitude index (PAx)-was calculated as the Pearson correlation between (averaged over 10 s intervals) ABP and AMP with a 5 min long moving average window. The previously introduced transcranial Doppler-based autoregulation index Mx was evaluated in a similar way, as the moving correlation between blood flow velocity and CPP. The clinical outcome was assessed after 6 months using the Glasgow outcome score. RESULTS: 293 patients were studied. The mean PAx was -0.09 (standard deviation 0.21). This negative value indicates that, on average, an increase in ABP causes a decrease in AMP and vice versa. PAx correlated strong with Mx (R (2) = 0.46, P < 0.0002). PAx also correlated with age (R (2) = 0.18, P < 0.05). PAx was found to have as good predictive outcome value (area under curve 0.71, P < 0.001) as Mx (area under curve 0.69, P < 0.001). CONCLUSIONS: We demonstrated significant correlation between the known cerebral autoregulation index Mx and PAx. This new index of cerebrovascular pressure reactivity using ICP pulse wave information showed to have a strong association with outcome in TBI patients.

ICM+, a flexible platform for investigations of cerebrospinal dynamics in clinical practice.

BACKGROUND: ICM+ software encapsulates 20 years of our experience in brain monitoring gained in multiple neurosurgical and intensive care centres. It collects data from a variety of bedside monitors and produces on-line time trends of parameters defined using configurable signal processing formulas. The resulting data can be displayed in a variety of ways including time trends, histograms, cross histograms, correlations, etc. For technically minded researchers there is a plug-in mechanism facilitating registration of third party libraries of functions and analysis tools. METHODS: The latest version of the ICM+ software has been used in 162 severely head injured patients in the Neurosciences Critical Care Unit of the Addenbrooke's Cambridge University Hospital. Intracranial pressure (ICP) and invasive arterial blood pressure (ABP) were monitored routinely. Mean values of ICP, ABP, cerebral perfusion pressure (CPP) and various indices describing pressure reactivity (PRx), pressure-volume compensation (RAP) and vascular waveforms of ICP were calculated. Error-bar chart showing reactivity index PRx versus CPP ('Optimal CPP' chart) was calculated continuously. FINDINGS: PRx showed a significant relationship with CPP (ANOVA: p < 0.021) indicating loss of cerebral pressure-reactivity for low CPP (CPP < 55 mmHg) and for high CPPs (CPP > 95 mmHg). Examining PRx-CPP curves in individual patients revealed that CPP(OPT) not only varied between subjects but tended to fluctuate as the patient's state changed during the stay in the ICU. Calculation window of 6-8 h provided enough data to capture the CPP(OPT) curve. CONCLUSIONS: ICM+ software proved to be useful both academically and clinically. The complexity of data analysis is hidden inside loadable profiles thus allowing clinically minded investigators to take full advantage of signal processing engine in their research into cerebral blood and fluid dynamics.

Pulse amplitude of intracranial pressure waveform in hydrocephalus.

BACKGROUND: There is increasing interest in evaluation of the pulse amplitude of intracranial pressure (AMP) in explaining dynamic aspects of hydrocephalus. We reviewed a large number of ICP recordings in a group of hydrocephalic patients to assess utility of AMP. MATERIALS AND METHODS: From a database including approximately 2,100 cases of infusion studies (either lumbar or intraventricular) and overnight ICP monitoring in patients suffering from hydrocephalus of various types (both communicating and non-communicating), etiology and stage of management (non-shunted or shunted) pressure recordings were evaluated. For subgroup analysis we selected 60 patients with idiopathic NPH with full follow-up after shunting. In 29 patients we compared pulse amplitude during an infusion study performed before and after shunting with a properly functioning shunt. Amplitude was calculated from ICP waveforms using spectral analysis methodology. FINDINGS: A large amplitude was associated with good outcome after shunting (positive predictive value of clinical improvement for AMP above 2.5 mmHg was 95%). However, low amplitude did not predict poor outcome (for AMP below 2.5 mmHg 52% of patients improved). Correlations of AMP with ICP and Rcsf were positive and statistically significant (N = 131 with idiopathic NPH; R = 0.21 for correlation with mean ICP and 0.22 with Rcsf; p< 0.01). Correlation with the brain elastance coefficient (or PVI) was not significant. There was also no significant correlation between pulse amplitude and width of the ventricles. The pulse amplitude decreased (p < 0.005) after shunting. CONCLUSIONS: Interpretation of the ICP pulse waveform may be clinically useful in patients suffering from hydrocephalus. Elevated amplitude seems to be a positive predictor for clinical improvement after shunting. A properly functioning shunt reduces the pulse amplitude.

The relationship between the intracranial pressure-volume index and cerebral autoregulation.

OBJECTIVE: The pressure-volume index (PVI) can be used to assess the cerebrospinal fluid dynamics and intracranial elastance in critically ill brain injured patients. The dependency of PVI on the state of cerebral autoregulation within the physiologic range of cerebral perfusion pressure (CPP) can be described by mathematical models that account for changes in cerebral blood volume during PVI testing. This relationship has never been verified clinically using direct PVI measurement and independent cerebral autoregulation assessment. DESIGN, SETTING, AND PATIENTS: PVI and cerebral autoregulation were prospectively assessed in a cohort of 19 comatose patients admitted to an academic intensive care unit in Brescia, Italy. INTERVENTION: None. METHODS: PVI was measured injecting a fixed volume of 2 ml of 0.9% sodium chloride solution into the cerebral ventricles through an intraventricular catheter. Cerebral autoregulation was assessed using transcranial Doppler transient hyperaemic response (THR) test. MEASUREMENTS AND RESULTS: Fifty-nine PVI assessments and 59 THR tests were performed. Mean PVI was 20.0 (SD 10.2) millilitres in sessions when autoregulation was intact (THR test >or=1.1) and 31.6 (8.8) millilitres in sessions with defective autoregulation (THR test <1.1) (DeltaPVI = 11.7 ml, 95% CI = 4.7-19.3 ml; P = 0.002). Intracranial pressure, CPP and brain CT findings were not significantly different between the measurements with intact and disturbed autoregulation. CONCLUSIONS: Cerebral autoregulation status can affect PVI estimation despite a normal CPP. PVI measurement may overestimate the tolerance of the intracranial system to volume loads in patients with disturbed cerebral autoregulation.

Cerebrospinal fluid dynamics: disturbances and diagnostics.

The pathophysiology of hydrocephalus can be modelled and described in terms of altered biomechanical parameters. Shunting is aimed to correct the patient's cerebrospinal fluid dynamics, compensating for inadequate cerebrospinal fluid re-absorption or insufficient volume buffering reserve. Computerized infusion studies implement intracranial pressure and arterial pressure signal processing and model analysis to allow the estimation of cerebrospinal dynamics variables such as cerebrospinal fluid outflow resistance, brain compliance and pressure-volume index, estimated sagittal sinus pressure, cerebrospinal fluid formation rate, compensatory reserve and cerebral vasoreactivity. Infusion studies can assist in the prognostication of normal pressure hydrocephalus and in the diagnosis of idiopathic intracranial hypertension. The technique is also helpful in the assessment of shunt malfunction, including posture-related over-drainage and shunt obstruction.

Transcranial Doppler ultrasonography in intensive care.

Transcranial Doppler is an innovative, flexible, accessible tool for the bedside monitoring of static and dynamic cerebral flow and treatment response. Introduced by Rune Aaslid in 1982, it has become indispensable in clinical practice. The main obstacle to ultrasound penetration of the skull is bone. Low frequencies, 1-2 MHz, reduce the attenuation of the ultrasound wave caused by bone. Transcranial Doppler also provides the advantage of acoustic windows representing specific points of the skull where the bone is thin enough to allow ultrasounds to penetrate. There are four acoustic windows: transtemporal, transorbital, suboccipital and retromandibular. The identification of each intracranial vessel is based on the following elements: (a) velocity and direction; (b) depth of signal capture; (c) possibility of following the vessel its whole length; (d) spatial relationship with other vessels; and (e) response to homolateral and contralateral carotid compression. The main fields of clinical application of transcranial Doppler are assessment of vasospasm, detection of stenosis of the intracranial arteries, evaluation of cerebrovascular autoregulation, non-invasive estimation of intracranial pressure, measure of effective downstream pressure and assessment of brain death. Mean flow velocity is directly proportional to flow and inversely proportional to the section of the vessel. Any circumstance that leads to a variation of one of these factors can thus affect mean velocity. The main pathological condition affecting flow velocity is the vasospasm. Vasospasm is a frequent complication of subarachnoid haemorrhage, it often remains clinically silent and the factors that make it symptomatic are largely unknown. Threshold velocities above which vasospasm comes into place are well defined as regards the median cerebral artery, while there is no consensus for the other vessels. Nevertheless, an increase in velocity alone is not sufficient to arrive at a diagnosis of vasospasm; a condition of hyperaemia also presents with an increase in flow velocity. The Lindegaard Index has therefore been introduced, which is defined by the ratio between the mean flow velocity in the median cerebral artery and the mean flow velocity in the internal carotid artery. Criteria for diagnosis of a stenosis >50% of an intracranial vessel with transcranial Doppler include: (a) segmentary acceleration of flow velocity; (b) drop in velocity below the stenotic segment; (c) asymmetry; and (d) circumscribed flow disturbances (turbulence and musical murmur). The transcranial Doppler enables us to assess both components of self-regulation. The static component is measured by observing changes in flow velocity caused by pharmacologically induced episodes of hypertension and hypotension. The dynamic component of autoregulation can be measured using a method devised by Aaslid known as the 'cuff test'. A very effective and safe device for measuring cerebral autoregulation is the transient hyperaemic response test. This test is based on the compensatory vasodilatation of the arterioles, which occurs after brief compression of the common carotid. Csonyka proposed the following formula based on clinical observation for the calculation of cerebral perfusion pressure: CPP = MAP x FVd/FVm + 14. Brain death is defined as the irreversible cessation of all functions of the whole brain. The clinical criteria are usually considered sufficient to establish a diagnosis of brain death; however, they might not be sufficient in patients who have been on sedatives or when there are ethical or legal controversies. Many authors have demonstrated the existence of a transcranial Doppler pattern, which is typical of brain death.

Clinical testing of CSF circulation.

Since shunting is almost a purely mechanical treatment that radically affects pressure-volume compensation, patients' cerebrospinal fluid hydrodynamics compensation should be examined before a shunt is implanted. Apart from an opening pressure and a resistance to cerebrospinal fluid outflow, pulse amplitude of intracranial pressure and the content of vasogenic waves are useful to gauge cerebrospinal fluid dynamics. Infusion studies, although invasive, may help with the decision about surgery. They also provide basic information for further management of shunted patients, when complications, such as shunt blockage, under- and over-drainage, arise.

Cerebrovascular reactivity during hypothermia and rewarming.

BACKGROUND: Experimental evidence from a murine model of traumatic brain injury (TBI) suggests that hypothermia followed by fast rewarming may damage cerebral microcirculation. The effects of hypothermia and subsequent rewarming on cerebral vasoreactivity in human TBI are unknown. METHODS: This is a retrospective analysis of data acquired during a prospective, observational neuromonitoring and imaging data collection project. Brain temperature, intracranial pressure (ICP), and cerebrovascular pressure reactivity index (PRx) were continuously monitored. RESULTS: Twenty-four TBI patients with refractory intracranial hypertension were cooled from 36.0 (0.9) to 34.2 (0.5) degrees C [mean (sd), P < 0.0001] in 3.9 (3.7) h. Induction of hypothermia [average duration 40 (45) h] significantly reduced ICP from 23.1 (3.6) to 18.3 (4.8) mm Hg (P < 0.05). Hypothermia did not impair cerebral vasoreactivity as average PRx changed non-significantly from 0.00 (0.21) to -0.01 (0.21). Slow rewarming up to 37.0 degrees C [rate of rewarming, 0.2 (0.2) degrees C h(-1)] did not increase ICP [18.6 (6.2) mm Hg] or PRx [0.06 (0.18)]. However, in 17 (70.1%) out of 24 patients, rewarming exceeded the brain temperature threshold of 37 degrees C. In these patients, the average brain temperature was allowed to increase to 37.8 (0.3) degrees C (P < 0.0001), ICP remained stable at 18.3 (8.0) mm Hg (P = 0.74), but average PRx increased to 0.32 (0.24) (P < 0.0001), indicating significant derangement in cerebrovascular reactivity. After rewarming, PRx correlated independently with brain temperature (R = 0.53; P < 0.05) and brain tissue O2 (R = 0.66; P < 0.01). CONCLUSIONS: After moderate hypothermia, rewarming exceeding the 37 degrees C threshold is associated with a significant increase in average PRx, indicating temperature-dependent hyperaemic derangement of cerebrovascular reactivity.