Vitamin D status and supplementation in adult patients receiving extracorporeal membrane oxygenation.

The prevalence of vitamin D deficiency in critical illness is known to be high and associated with adverse clinical outcomes. Patients receiving extracorporeal membrane oxygenation (ECMO) may be at increased risk of vitamin D deficiency due to high severity of acute illness. Challenges with drug dosing in ECMO patients are recognised due to increased volume of distribution and drug absorption to circuit components. To describe the prevalence of vitamin D deficiency in ECMO patients and the effect of intramuscular dosing of cholecalciferol on levels of vitamin D metabolites, and to compare these data with intensive care unit (ICU) patients not receiving ECMO, two prospective studies were performed sequentially: an observational study of 100 consecutive ICU patients and an interventional study assessing effects of intramuscular cholecalciferol in 50 ICU patients. The subgroup of patients who required ECMO support in each of these studies was analysed and compared to patients who did not receive ECMO. Twenty-four ECMO patients, 12 from the observational study and 12 from the interventional study (who received intramuscular cholecalciferol) were studied-21/24 (88%) ECMO patients were vitamin D deficient at baseline compared to 65/126 (52%) of non-ECMO patients (P=0.006). Of the 12 ECMO patients who received cholecalciferol, six patients (50%) achieved correction of deficiency compared to 36/38 (95%) non-ECMO patients (P=0.001). The prevalence of vitamin D deficiency is higher in ECMO patients compared to other critically ill adults. Correction of deficiency with single dose cholecalciferol is not reliable; higher or repeated doses should be considered to correct deficiency.

Fluid resuscitation in acute medicine: what is the current situation?

The administration of intravenous fluids for resuscitation is the most common intervention in acute medicine. There is increasing evidence that the type of fluid may directly affect patient-centred outcomes. There is a lack of evidence that colloids confer clinical benefit over crystalloids and they may be associated with harm. Hydroxyethyl starch preparations are associated with increased mortality and use of renal replacement therapy in critically ill patients, particularly those with sepsis; albumin is associated with increased mortality in patients with severe traumatic brain injury. Crystalloids, such as saline or balanced salt solutions, are increasingly recommended as first-line resuscitation fluids for the majority of patients with hypovolaemia. There is emerging evidence that saline may be associated with adverse outcomes due to the development of hyperchloraemic metabolic acidosis, although the safety of balanced salt solutions has not been established. Fluid requirements vary over the course of critical illness. The excessive use of fluids during the resuscitative period is associated with increased cumulative fluid balance and adverse outcomes in critically ill patients. The selection of fluid depends on the clinical context in which it is administered and requires careful consideration of the dose and potential for toxicity. There is an urgent need to conduct further high-quality randomized controlled trials of currently available fluid therapy in patients with critical illness.

International albumin use: 1995 to 2006.

Over the last ten years more reliable information regarding the risks and benefits of the use of albumin for fluid resuscitation has emerged. To determine what influence this has had on clinical practice, we sought to document albumin use (from mass of albumin supplied to hospitals) in 16 industrialised countries between 1995 and 2006. Data on national albumin and synthetic colloid use was sought from independent intensive care researchers and albumin issuers. The mass of albumin supplied per 10,000 persons on an annual basis by country and aggregated across the study countries was calculated. Volumes of synthetic colloid supplied per 10,000 persons were calculated. Data were obtained for 15 countries. Albumin use varied significantly between countries and throughout the observation period. Overall, aggregate albumin use decreased from a peak of 2.54 kg per 10,000 persons in 1995 to 1.40 kg per 10,000 persons in 1999; use has remained relatively constant since. Data on supply of synthetic colloids was available in only three countries and varied from 11.7 litres per 10,000 persons in Canada in 1995, to 231.8 litres per 10,000 persons in Denmark in 2004. Between 1995 and 1999 albumin use decreased and has been materially constant since; where data were available, use of synthetic colloids increased. Whether these practice changes have resulted in a net health gain or in harm requires further research.

Crisis management during anaesthesia: sepsis.

BACKGROUND: Anaesthesia with concurrent sepsis is risky, and involves consideration of possible organ dysfunctions-respiratory, cardiovascular, renal, and haematological--as well as ensuring that appropriate antibiotics are given after taking the necessary microbiological specimens. Because prompt attention needs to be paid to so many body systems, the place for a structured approach during anaesthesia for a septic patient was assessed. OBJECTIVES: To examine the role of a previously described core algorithm "COVER ABCD-A SWIFT CHECK", supplemented by a specific sub-algorithm for sepsis, in the management of sepsis occurring in association with anaesthesia. METHODS: The potential performance of this structured approach for each of the relevant incidents among the first 4000 reported to the Australian Incident Monitoring Study (AIMS) was compared with the actual management as reported by the anaesthetists involved. RESULTS: Sepsis was identified as the primary problem in 13 of the first 4000 reports (<1%) to AIMS. The incidents reported generally occurred in sick patients; 70% were ASA status III or worse. The COVER ABCD algorithm provided a diagnosis and corrective manoeuvre in only 15% (2/13) of reported incidents, and the sepsis sub-algorithm provided adequate therapeutic strategies in a further 38% (5/13) of the incidents. Eight cases required the use of additional sub-algorithms for desaturation (30%), cardiac arrest (15%), hypotension (8%), and aspiration (8%). CONCLUSION: Sepsis involves a serious physiological stress upon multiple organ systems. The use of a structured approach involving a core algorithm and additional sub-algorithms as required provides a series of checklists that can successfully deal with the complex multiple and interrelating problems that these patients present.

Crisis management during anaesthesia: regurgitation, vomiting, and aspiration.

BACKGROUND: Regurgitation, vomiting and aspiration may occur unexpectedly in association with anaesthesia. "Aspiration/regurgitation" was ranked fifth in a large collection of previously reported incidents that arose during general anaesthesia. These problems are encountered by all practising anaesthetists and require instant recognition and a rapid, appropriate response. However, the diagnosis may not be immediately apparent as the initial presentation may vary from laryngospasm, desaturation, bronchospasm or hypoventilation to cardiac arrest. OBJECTIVES: To examine the role of a previously described core algorithm "COVER ABCD-A SWIFT CHECK", supplemented by a specific sub-algorithm for regurgitation, vomiting and aspiration, in the management of these complications occurring in association with anaesthesia. METHODS: The potential performance of this structured approach for each of the relevant incidents among the first 4000 reported to the Australian Incident Monitoring Study (AIMS) was compared with the actual management as reported by the anaesthetists involved. RESULTS: There were 183 relevant incidents of regurgitation, vomiting and aspiration among the first 4000 reports to the AIMS. Aspiration was documented in 96, was excluded in 69, and in 18 it could not be determined whether or not aspiration had occurred. It was considered that the correct use of an explicit algorithm would have led to earlier recognition and/or better management of the problem in 10% of all cases of regurgitation and vomiting and in 19% of those in which aspiration occurred. CONCLUSION: Regurgitation and/or aspiration should always be considered immediately in any spontaneously breathing patient who suffers desaturation, laryngospasm, airway obstruction, bronchospasm, bradycardia, or cardiac arrest. Any patient in whom aspiration is suspected must be closely monitored in an appropriate perioperative facility, the acuity of which will depend on local staffing and workload. If clinical instability is likely to persist or if there are concerns by attending staff, the patient should be admitted to a high dependency unit or intensive care unit.

Crisis management during anaesthesia: pulmonary oedema.

BACKGROUND: Pulmonary oedema may complicate the perioperative period and the aetiology may be different from non-operative patients. Diagnosis may be difficult during anaesthesia and consequently management may be delayed. OBJECTIVES: To examine the role of a previously described core algorithm "COVER ABCD-A SWIFT CHECK", supplemented by a specific sub-algorithm for pulmonary oedema, in its management occurring in association with anaesthesia. METHODS: The potential performance of this structured approach for each of the relevant incidents among the first 4000 reported to the Australian Incident Monitoring Study (AIMS) was compared with the actual management as reported by the anaesthetists involved. RESULTS: Pulmonary oedema was identified in 35 (<1%) of the first 4000 reports to AIMS. The most frequent presenting sign was hypoxia (46%) and the most specific sign was the presence of frothy sputum (23%). The core algorithm, although successful in the management of the initial physiological upset, was found to be inadequate for the ongoing management of pulmonary oedema. A specific sub-algorithm for the management of perioperative pulmonary oedema was devised, tested against the reports and would have been effective, if properly applied, in the management of all but one of the reported cases. CONCLUSION: Successful recognition and management of perioperative pulmonary oedema is likely with the application of the structured algorithm and specific sub-algorithm approach outlined in this study.

Rat hepatoproliferin revealed the status of a complete hepatomitogen in human hepatoma cells.

Hepatoproliferin (HPF), a liver regeneration factor isolated from rat hepatocytes, was assessed for its mitogenic status in the human hepatoma cell line PLC/PRF-5. HPF was able to enhance hepatoma cell growth on its own without the aid of the established complete mitogens EGF and TGF-alpha or the hepato-priming factor TNF-alpha. HPF therefore acted as a complete hepatomitogen and had no co-mitogenic properties since it did not augment proliferation when combined with EGF or TGF-alpha but showed only an additive effect in the presence of TGF-alpha. Rat HPF was phylogenetically unrestricted, because it was found active in human cells. When each of the established growth factors (GFs) was used alone, the hepatoma cells responded with the same kind of response profile, namely a bi-phasic bell-shaped dose-dependent response due to stimulation at low levels and inhibition at higher levels. However, hepatocyte growth factor (HGF) was an exception since it did not induce a growth response in hepatoma cells. On the contrary HPF, on its own, showed a progressive enhanced linear dose response at the levels used for the GFs (ie 1.0-15 ng/5 x 10(5) cells). The comparative potency (CP) (dpm x 10(3)/microg DNA/ng GF) of HPF (CP = 13) was in the same range as for the complete hepatomitogens EGF (CP = 12) and TGF-alpha (CP = 14), revealing that HPF has indeed the status of a complete mitogen.

Driving cerebral perfusion pressure with pressors: how, which, when?

In traumatic brain injury, cerebral hypoperfusion is associated with adverse outcome, particularly in the early phases of management. This has resulted in the increased use of drugs such as adrenaline, noradrenaline, dopamine and phenylephrine to augment or maintain systemic blood pressures at near normal levels. This is now part of standard practice and is endorsed by the Brain Trauma Foundation guidelines. It probably matters little which agent is used, provided appropriate monitoring is in place and those reversible causes of hypotension are promptly excluded and treated. However, blindly applying management guidelines to all patients may negate these early benefits. The time has come move away from artificially separated concepts of "intracranial pressure" versus "cerebral perfusion pressure" based strategies. These should be considered in parallel and applied to an individual patient, rather than making the patient fit into an all-encompassing treatment algorithm. . A paradigm shift from a "set and forget" philosophy to one of "titration against time" to achieve appropriate therapeutic targets is now required. In this context the rational use of vasoactive agents to optimise cerebral perfusion pressure may be employed. On the basis of limited animal and human evidence, noradrenaline appears to be the most appropriate catecholamine for traumatic brain injury, although definitive, targeted trials are required.

"Triple h" therapy for aneurysmal subarachnoid haemorrhage: real therapy or chasing numbers?

Despite technological and medical advances for the treatment of SAH that have had a positive impact on outcomes over the last 20 years, but the all-cause mortality for this often-catastrophic condition remains high at 12 - 15%. Survival will ultimately depend on the severity of the haemorrhage, the subsequent loss of functional neurones and the extracranial reserve of the patient. In this regard, advances in neuroradiology and operative techniques together with expert neurocritical care and rehabilitation provide the best chances of short- and long- term survival respectively. In this context, the contribution of cerebral vasospasm to attributable morbidity and mortality remains conjectural albeit real, and whilst medical anti-vasospastic therapies should be considered in vulnerable patients, they should be used with circumspection and caution. There is little or no evidence to justify the aggressive use of anti-vasospastic therapies as a preventative manner with exception of oral nimodipine in patients with low-grade aneurysmal subarachnoid haemorrhage. Concomitant use of induced hypertension/hypervolaemia/haemodilution cannot be recommended on current evidence, but if employed should be done on an individualised basis, considering the patients underlying neurological condition, cardiopulmonary reserve, adequacy of systemic and neurological monitoring and access to expert neuroradiological, neurosurgical and neurocritical care services.

Quantifying cerebral autoregulation in health and disease.

OBJECTIVE: To review methods of quantifying human cerebral autoregulation in health and disease. DATA SOURCES: Articles and published abstracts on methods to quantify cerebral autoregulation in health and disease. SUMMARY OF REVIEW: Cerebral autoregulation is defined as the relationship between cerebral blood flow and cerebral perfusion pressure. Complex neurohumoral processes are involved in myogenic and metabolic mechanisms to maintain cerebral blood flow at a constant level in the presence of fluctuating systemic and cerebral perfusion pressures. Despite advances in physiological measurement, there is no standard measurement of cerebral blood flow and quantifying cerebral autoregulation remains problematic. Clinical monitors such as transcranial Doppler and jugular bulb oximetry have high levels of error with poor specificity and sensitivity. Cerebral autoregulation is impaired in traumatic brain injury and subarachnoid haemorrhage, so that cerebral blood flow becomes pressure-passive. Hypotension is associated with significant secondary neuronal damage following traumatic brain injury. Hypertensive emergencies represent failure of the upper autoregulatory threshold, often with devastating neurological consequences. The monitoring and treatment of autoregulatory failure remains limited and is essentially directed at maintaining an appropriate systemic blood pressure. Consequently, the use of strategies to manipulate cerebral perfusion requires care and circumspection. CONCLUSIONS: Cerebral autoregulation is impaired with brain injury with cerebral blood flow often becoming pressure-passive. The monitoring and treatment of autoregulatory failure is limited and usually directed at maintaining systemic blood pressure with the effectiveness of this strategy often being unknown.

Recombinant activated factor VII for exsanguinating haemorrhage post bilateral lung transplantation for extra-corporeal lung support-dependent respiratory failure.

Following three weeks of extracorporeal lung support for acute respiratory distress syndrome, a 15-year-old male underwent bilateral lung transplantation. This procedure was complicated by massive postoperative haemorrhage. The administration of recombinant activated Factor VII was associated with improved haemostasis. However, development of cardiac tamponade soon after injection required emergency exploration and evacuation of a large mediastinal clot.

The effect of infusions of adrenaline, noradrenaline and dopamine on cerebral autoregulation under isoflurane anaesthesia in an ovine model.

The effects of infusions of adrenaline, noradrenaline and dopamine on cerebral autoregulation under steady-state isoflurane anaesthesia were compared with the awake state. Six studies each were conducted in two cohorts of adult ewes: awake sheep and those anaesthetized with 2% isoflurane anaesthesia. In random order, each animal received ramped infusions of adrenaline, noradrenaline (0-40 micrograms/min) and dopamine (0-40 micrograms/kg/min). Cerebral blood flow was measured continuously from changes in Doppler velocities in the sagittal sinus. Autoregulation was determined by linear regression analysis between cerebral blood flow and mean arterial pressure. Isoflurane did not significantly alter cerebral blood flow relative to pre-anaesthesia values (P > 0.05). All three catecholamines significantly and equivalently increased MAP from baseline in a dose dependent manner in both the awake and isoflurane cohorts. Although adrenaline significantly increased cerebral blood flow from baseline in the awake cohort (P < 0.01), none of the catecholamines significantly increased cerebral blood flow during isoflurane anaesthesia. No significant differences were demonstrated between the slopes and intercepts of regression lines for adrenaline, noradrenaline and dopamine within either cohort (ANCOVA). Inter-cohort comparisons between the two autoregulation curves demonstrated no significant difference between the slopes of the autoregulation curves for the awake (pooled slope = 0.39) and isoflurane cohorts (pooled slope = 0.28) (P > 0.05). Over a specific dose range, systemic hypertension induced by adrenaline, noradrenaline and dopamine did not significantly increase cerebral blood flow under 2% isoflurane anaesthesia. The concomitant administration of isoflurane and the catecholamines was not associated with altered autoregulatory function compared to the awake state.

Antibiotic prophylaxis for external ventricular drains in neurosurgical patients: an audit of compliance with a clinical management protocol.

OBJECTIVE: To examine the clinical impact of a management protocol for external ventricular drains (EVD). PATIENTS AND METHODS: All patients with EVDs over a six-month period were reviewed retrospectively. Data concerning the indications for EVD placement, antibiotics and cerebrospinal fluid (CSF) analyses were collected. A restrictive antibiotic protocol (e.g. intravenous cephalothin 1g 6-hourly for 24 hours, unless other antibiotics were prescribed for a documented pre-existing infection) was introduced for all patients requiring placement of an EVD during the following six months and all patients were observed prospectively. Daily CSF samples were collected under sterile conditions and examined for organisms, cells, glucose and protein and sent for microbiological culture. External ventricular drains were removed after five days and replaced if further monitoring or CSF drainage was required. Adherence to the protocol and the incidence of ventriculitis was determined. RESULTS: Twelve patients with EVDs were identified during the 6 month pre-protocol period and 15 patients with EVDs were identified during the 6 month post-protocol period. There was no significant difference between the total (72 vs 88 days) and mean (6 vs 5.9 days) drain placement times between the two groups. There was no significant difference between the mean numbers of CSF samples in the two groups. CSF aspirates were not analysed in 35/72 samples (49%) in the pre-protocol group compared with 45/88 (51%) samples in the post-protocol group. Positive CSF Gram-stains were found in 3/12 (25%) patients in the pre-protocol group and in 0/15(0%) in the post-protocol group. Positive CSF cultures decreased significantly in the post-protocol group (17 vs 5, p = 0.0009). Prophylactic antibiotics were prescribed in 5/12 (42%) patients in the pre-protocol group compared with 12/15 (80%) patients in the post-protocol group. CONCLUSIONS: The protocol was associated with a statistically significant improvement in compliance with antibiotic prescription and reduction in the incidence of positive CSF cultures.

The cerebrovascular effects of adrenaline, noradrenaline and dopamine infusions under propofol and isoflurane anaesthesia in sheep.

Infusions of catecholamines are frequently administered to patients receiving propofol or isoflurane anaesthesia. Interactions between these drugs may affect regional circulations, such as the brain. The aim of this animal (sheep) study was to determine the effects of ramped infusions of adrenaline, noradrenaline (10, 20, 40 micrograms/min) and dopamine (10, 20, 40 micrograms/kg/min) on cerebral blood flow (CBF), intracranial pressure (ICP), cerebrovascular resistance (CVR) and cerebral metabolic rate for oxygen (CMRO2). These measurements were made under awake physiological conditions, and during continuous propofol (15 mg/min) or 2% isoflurane anaesthesia. All three catecholamines significantly and equivalently increased mean arterial pressure from baseline in a dose-dependent manner in the three cohorts (P < 0.001). In the awake cohort (n = 8), dopamine (P < 0.01) significantly increased CBF from baseline whilst adrenaline and noradrenaline did not (P > 0.05). Under propofol (n = 6) and isoflurane (n = 6), all three catecholamines significantly increased CBF (P < 0.001). Dopamine caused the greatest increase in CBF, and was associated with significant increases in ICP (awake: P < 0.001; propofol P < 0.05; isoflurane P < 0.001) and CVR (isoflurane P < 0.05). No significant changes in CMRO2 were demonstrated. Under propofol and isoflurane anaesthesia, the cerebrovascular effects of catecholamines were significantly different from the awake, physiological state, with dopamine demonstrating the most pronounced effects, particularly under propofol. Dopamine-induced hyperaemia was associated with other cerebrovascular changes. In the presence of an equivalent effect on mean arterial pressure, the exaggerated cerebrovascular effects under anaesthesia appear to be centrally mediated, possibly induced by propofol- or isoflurane-dependent changes in blood-brain barrier permeability, thereby causing a direct influence on the cerebral vasculature.

Cerebrovascular carbon dioxide reactivity in sheep: effect of propofol or isoflurane anaesthesia.

Propofol and isoflurane are commonly used in neuroanaesthesia. Some published data suggest that the use of these agents is associated with impaired cerebral blood flow/carbon dioxide (CO2) reactivity. Cerebrovascular CO2 reactivity was therefore measured in three cohorts of adult merino sheep: awake (n=6), anaesthetized with steady-state propofol (15 mg/min; n=6) and anaesthetized with 2% isoflurane (n=6). Changes in cerebral blood flow were measured continuously from changes in velocities of blood in the sagittal sinus via a Doppler probe. Alterations in the partial pressure of carbon dioxide in arterial blood (PaCO2) over the range 18-63 mmHg were achieved by altering either the inspired CO2 concentration or the rate of mechanical ventilation. Cerebral blood flow/CO2 relationships were determined by linear regression analysis, with changes in cerebral blood flow expressed as a percentage of the value for a PaCO2 of 35 mmHg. Propofol decreased cerebral blood flow by 55% relative to pre-anaesthesia values (P=0.0001), while isoflurane did not significantly alter cerebral blood flow (88.45% of baseline, P=0.39). Significant linear relationships between cerebral blood flow and CO2 tension were determined in all individual studies (r2 ranged from 0.72 to 0.99). The slopes of the lines were highly variable between individuals for the awake cohort (mean 4.73, 1.42-7.12, 95% CI). The slopes for the propofol (mean 2.67, 2.06-3.28, 95% CI) and isoflurane (mean 2.82, 219-3.45, 95% CI) cohorts were more predictable. However, there was no significant difference between these anaesthetic agents with respect to the CO2 reactivity of cerebral blood flow.

Tolerance in baboon kidney transplantation with total lymphoid irradiation (TLI) and anti-CD3/CD4-idarubicin conjugates.

BACKGROUND: We previously reported the induction of transplantation tolerance by a modified wide field method of pretransplant total lymphoid irradiation (TLI), cumulative dose 800 cGy, given as 80 or 100 cGy fractions twice/week, in approximately one-third of chacma baboons receiving liver or kidney allografts (1-4) and in vervet monkeys receiving baboon kidney xenografts (5). In this study, the effects of the administration of brief courses of anti-CD3 or CD4-Idarubicin conjugates on the frequency and predictability of tolerance induction by TLI were examined. METHODS: TLI was administered pretransplant in doses of 800, 600, or 400 cGy. The conjugates were administered either after transplantation in doses of 0.25 mg/kg body weight, 3 times/week for 2 weeks, or as a single dose of 1.0 mg/kg body weight 24 hr before transplantation. RESULTS: Operational tolerance, defined as normal graft function >1 year after transplantation, was obtained in one-half of six baboons receiving the single dose of 1 mg/kg of Idarubicin conjugate pretransplant after 800 cGy of TLI and also in one of four baboons treated with 400 cGy of TLI and a single dose of anti-CD3 conjugate before transplantation. By contrast, administration of the conjugated antibodies 3 times/week for 2 weeks after transplantation prevented tolerance induction in all animals, providing further evidence for the involvement of active mechanisms, capable of inhibition by immunosuppressive agents, in tolerance induction with TLI, and of relevance to our reported clinical experience with TLI (6). CONCLUSIONS: These promising findings invite further studies with a larger number of animals and additional brief regimens of irradiation and antibody dosages and specificities.