The interaction of vasopressin and corticosteroids in septic shock: a pilot randomized controlled trial.

OBJECTIVES: Vasopressin and corticosteroids are both commonly used adjunctive therapies in septic shock. Retrospective analyses have suggested that there may be an interaction between these drugs, with higher circulating vasopressin levels and improved outcomes in patients treated with both vasopressin and corticosteroids. We aimed to test for an interaction between vasopressin and corticosteroids in septic shock. DESIGN: Prospective open-label randomized controlled pilot trial. SETTING: Four adult ICUs in London teaching hospitals. PATIENTS: Sixty-one adult patients who had septic shock. INTERVENTIONS: Initial vasopressin IV infusion titrated up to 0.06 U/min and then IV hydrocortisone (50 mg 6 hourly) or placebo. Plasma vasopressin levels were measured at 6-12 and 24-36 hours after hydrocortisone/placebo administration. MEASUREMENTS AND MAIN RESULTS: Thirty-one patients were allocated to vasopressin + hydrocortisone and 30 patients to vasopressin + placebo. The hydrocortisone group required a shorter duration of vasopressin therapy (3.1 d; 95% CI, 1.1-5.1; shorter in hydrocortisone group) and required a lower total dose of vasopressin (ratio, 0.47; 95% CI, 0.32-0.71) compared with the placebo group. Plasma vasopressin levels were not higher in the hydrocortisone group compared with the placebo group (64 pmol/L difference at 6- to 12-hour time point; 95% CI, -32 to 160 pmol/L). Early vasopressin use was well tolerated with only one serious adverse event possibly related to study drug administration reported. There were no differences in mortality rates (23% 28-day mortality in both groups) or organ failure assessments between the two treatment groups. CONCLUSIONS: Hydrocortisone spared vasopressin requirements, reduced duration, and reduced dose, when used together in the treatment of septic shock, but it did not alter plasma vasopressin levels. Further trials are needed to assess the clinical effectiveness of vasopressin as the initial vasopressor therapy with or without corticosteroids.

The effect of intravenous interferon-beta-1a (FP-1201) on lung CD73 expression and on acute respiratory distress syndrome mortality: an open-label study.

BACKGROUND: Pulmonary vascular leakage occurs early in acute respiratory distress syndrome (ARDS). Mortality is high (35-45%), but no effective pharmacotherapy exists. Production of anti-inflammatory adenosine by ecto-5'-nucleotidase (CD73) helps maintain endothelial barrier function. We tested whether interferon-beta-1a (IFN-beta-1a), which increases CD73 synthesis, can reduce vascular leakage and mortality in patients with ARDS. METHODS: In ex-vivo studies, we first established that IFN-beta-1a induced CD73 up-regulation in cultured human lung tissue samples. We then tested the safety, tolerability, and efficacy of intravenous human recombinant IFN-beta-1a (FP-1201) in patients with ARDS in an open-label study (comprising dose-escalation and expansion phases). We recruited patients from eight intensive care units in the UK. Eligible patients were aged 18 years or older, had ARDS, and were being treated with assisted ventilation. We established an optimal tolerated dose (OTD) in the first, dose-escalation phase. Once established, we gave all subsequently enrolled patients the OTD of intravenous FP-1201 for 6 days. We assessed 28-day mortality (our primary endpoint) in all patients receiving the OTD versus 28-day mortality in a group of patients who did not receive treatment (this control group comprised patients in the study but who did not receive treatment because they were screened during the safety windows after dose escalation). This trial is registered with ClinicalTrials.gov, number NCT00789685, and the EU Clinical Trials Register EudraCT, number 2008-000140-13. FINDINGS: IFN-beta-1a increased the number of CD73-positive vessels in lung culture by four times on day 1 (p=0·04) and by 14·3 times by day 4 (p=0·004). For the clinical trial, between Feb 23, 2009, and April 7, 2011, we identified 150 patients, of whom 37 were enrolled into the trial and given treatment. The control group consisted of 59 patients who were recruited to take part in the study, but who did not receive treatment. Demographic characteristics and severity of illness did not differ between treatment and control groups. The optimal tolerated FP-1201 dose was 10 µg per day for 6 days. By day 28, 3 (8%) of 37 patients in the treatment cohort and 19 (32%) of 59 patients in the control cohort had died-thus, treatment with FP-1201 was associated with an 81% reduction in odds of 28-day mortality (odds ratio 0·19 [95% CI 0·03-0·72]; p=0·01). INTERPRETATION: FP-1201 up-regulates human lung CD73 expression, and is associated with a reduction in 28-day mortality in patients with ARDS. Our findings need to be substantiated in large, prospective randomised trials, but suggest that FP-1201 could be the first effective, mechanistically targeted, disease-specific pharmacotherapy for patients with ARDS.

Cardiorespiratory arrest secondary to tracheostomy cuff herniation.

This report details the case of a 67-year-old man who required intubation following a fall and multiple rib fractures and underwent surgical tracheostomy. Postoperatively, he deteriorated on the intensive care unit with airway obstruction. Bronchoscopy demonstrated tracheostomy cuff herniation obstructing airflow necessitating conventional orotracheal reintubation. On inspection of the tracheostomy an unusual cuff deformation was noted.

Lactate in cystic fibrosis sputum.

BACKGROUND: Antibiotic therapy is thought to improve lung function in patients with cystic fibrosis (CF) by decreasing neutrophil-derived inflammation. We investigated the origin and clinical significance of lactate in the chronically inflamed CF lung. METHODS: Lactate was measured in sputa of 18 exacerbated and 25 stable CF patients via spectrophotometry and gaschromatography. Lung function was assessed via spirometry. Seven patients with chronic obstructive pulmonary disease (COPD) and three patients with acute lung inflammation served as control groups. Neutrophil and bacterial lactate production was assessed under aerobic and anaerobic conditions. RESULTS: In sputum specimens of patients with respiratory exacerbations lactate concentrations decreased significantly (p<0.005) from 3.4±2.3mmol/L to 1.4±1.4mmol/L after 2-3 weeks of intravenous antibiotics. Successful treatment was reflected in 16 patients (88.9%) by FVC increase associated with lactate decrease (p<0.05). In every single sputum lactate was detectable (3.0±3.1mmol/L, range 0.2-14.1mmol/L). Lactate was lower (1.6±0.8mmol/L) in sputa from seven COPD patients, and it was below the detection limit in three patients with acute lung inflammation. Neutrophil lactate production accumulated up to 10.5mmol/L after 4 days, whereas bacterial lactate production did not appear to contribute substantially to sputum lactate concentrations. CONCLUSIONS: Successful antibiotic therapy is reflected by a decrease in lactate concentrations. Neutrophils are the most likely source for lactate in sputum of CF patients. Therefore lactate may be used to monitor responses to antibiotic therapy as an adjunct to lung function measurements.

Survival in critical illness is associated with early activation of mitochondrial biogenesis.

RATIONALE: We previously reported outcome-associated decreases in muscle energetic status and mitochondrial dysfunction in septic patients with multiorgan failure. We postulate that survivors have a greater ability to maintain or recover normal mitochondrial functionality. OBJECTIVES: To determine whether mitochondrial biogenesis, the process promoting mitochondrial capacity, is affected in critically ill patients. METHODS: Muscle biopsies were taken from 16 critically ill patients recently admitted to intensive care (average 1-2 d) and from 10 healthy, age-matched patients undergoing elective hip surgery. MEASUREMENTS AND MAIN RESULTS: Survival, mitochondrial morphology, mitochondrial protein content and enzyme activity, mitochondrial biogenesis factor mRNA, microarray analysis, and phosphorylated (energy) metabolites were determined. Ten of 16 critically ill patients survived intensive care. Mitochondrial size increased with worsening outcome, suggestive of swelling. Respiratory protein subunits and transcripts were depleted in critically ill patients and to a greater extent in nonsurvivors. The mRNA content of peroxisome proliferator-activated receptor γ coactivator 1-α (transcriptional coactivator of mitochondrial biogenesis) was only elevated in survivors, as was the mitochondrial oxidative stress protein manganese superoxide dismutase. Eventual survivors demonstrated elevated muscle ATP and a decreased phosphocreatine/ATP ratio. CONCLUSIONS: Eventual survivors responded early to critical illness with mitochondrial biogenesis and antioxidant defense responses. These responses may partially counteract mitochondrial protein depletion, helping to maintain functionality and energetic status. Impaired responses, as suggested in nonsurvivors, could increase susceptibility to mitochondrial damage and cellular energetic failure or impede the ability to recover normal function. Clinical trial registered with clinical trials.gov (NCT00187824).

Cellular processes in sepsis.

Sepsis, the systemic inflammatory response to an infection, is an increasingly common condition. It represents a major healthcare problem as affected patients have a high morbidity and mortality leading to high direct and indirect costs. This article describes the progression from a simple infection to septic shock and multi-organ failure, with a special emphasis on the body's response at the cellular level. Pathogen recognition by the host is followed by a cascade of pro- and anti-inflammatory mediators that attempt to defend the body and prevent further harm. Both pathogen virulence and host resistance regulate the severity of the inflammatory response. As a result of the inflammatory insult, mitochondria are damaged functionally and structurally. Since mitochondria are responsible for intracellular energy production, mitochondrial dysfunction places the cells at risk of developing energy failure and, consequently, cell death. However, sepsis is characterised by a lack of tissue necrosis and the ability of most - if not all - organs to recover completely. This underlines the assumption that organ dysfunction during sepsis is predominantly a functional problem which appears to relate to the creation of a new balance between energy generation and expenditure. Hence, organ dysfunction could be viewed as a protective mechanism for the patient and may represent a state analogous to hibernation, which can be reversed once the infection is overcome and inflammation has abated. More research is needed to develop better directed and timed therapeutic interventions that can reduce the high morbidity and mortality of this common condition.

Tissue oxygen and hemodynamics in renal medulla, cortex, and corticomedullary junction during hemorrhage-reperfusion.

Previous studies of intrarenal perfusion and tissue oxygenation have produced a wide range of results and have not matched tissue oxygen tension (tPo(2)) with concurrent changes in flow in three distinct regions. We thus used an anesthetized rat model of hemorrhage-reperfusion to address this question. Combined tpo(2)/laser-Doppler fiber-optic probes were simultaneously sited in cortical, corticomedullary (CMJ), and medullary regions of the left kidney. Total renal blood flow was measured in separate experiments. Recordings were made during exsanguination of 10 and 20% of estimated blood volume at 10-min intervals, followed by shed-blood resuscitation after a further 10 min. The decay in tpo(2) was then recorded following total cessation of blood flow, allowing estimation of local oxygen consumption. During exsanguination, tPo(2) was maintained in all intrarenal regions, despite significant falls in blood pressure and total renal blood flow. However, intrarenal flow was redistributed with reduced cortical, unchanged CMJ, and increased medullary blood flow. After resuscitation, significant rises above baseline were seen in blood pressure and in tpo(2) across all regions. Whereas cortical and medullary flows regained baseline values, CMJ flow fell. The ratio of tpo(2) to microvascular blood flow increased significantly in all regions during resuscitation, suggesting decreased oxygen consumption. On total cessation of blood flow, the cortex and CMJ showed significant increases in the oxygen decay half-life, consistent with decreased consumption. To our knowledge, this is the first quantitative demonstration of a markedly heterogeneous intrarenal cardiorespiratory response to a hemodynamic insult, with effects most marked at the corticomedullary junction.

Transcutaneous PCO2 monitoring in critically ill adults: clinical evaluation of a new sensor.

OBJECTIVE: In critically ill patients, arterial blood gas analysis is the gold standard for evaluating systemic oxygenation and carbon dioxide partial pressure. A new miniaturized carbon dioxide tension Pco2-Spo2 single sensor (TOSCA, Linde Medical Sensors AG, Basel, Switzerland) continuously and noninvasively (transcutaneously) monitors both Paco2 and oxygen saturation by pulse oximetry (Spo2). The present study was designed to investigate the usability and the accuracy of this device in critically ill patients. DESIGN: Prospective clinical investigation. SETTING: A 20-bed, university-affiliated, surgical intensive care unit. PATIENTS: Patients admitted after major surgery, multiple trauma, or septic shock equipped with an arterial catheter. INTERVENTIONS: The heated (42 degrees C) sensor was fixed at the earlobe using an attachment clip. Transcutaneous Pco2 (TcPco2) measurements were correlated with Paco2 values (measured using a blood gas analyzer). In addition, the differences between Paco2 and TcPco2 values were evaluated using the method of Bland-Altman. MEASUREMENTS AND MAIN RESULTS: We studied 55 patients, aged 18-80 (mean 57 +/- 15) yrs. A total of 417 paired measurements were compared. Correlation between TcPco2 and Paco2 was r = .86 (p < .01) in the Paco2 range of 24-101 mm Hg. Mean bias (+/-sd) between the two methods of measurement (Bland-Altman analysis) was 1.2 +/- 6.0 mm Hg with TcPco2 slightly overestimating arterial carbon dioxide tension. Nineteen percent of the measured values were outside of the acceptable clinical range of agreement of +/-7.5 mm Hg. CONCLUSIONS: The present study suggests that Paco2 can be acceptably assessed by measuring TcPco2 using the TOSCA Pco2-Spo2 sensor.

Acute management of a cyanotic episode in an infant after a Norwood procedure.

In infants with a Norwood stage I reconstruction, the respiratory management to direct pulmonary to systemic blood flow ratio is of critical importance. Disturbance of this delicate blood-flow balance can occur causing rapid deterioration of the infant's condition requiring urgent interventions. However, the emergency staff personnel that are generally the first to be called may not be familiar with these patients' complex pathophysiology. We report on the resuscitation of an infant with a Norwood circulation who developed deep central cyanosis in an out-of-hospital environment. The infant deteriorated because of stenoses in both the neoaortic arch and the aortopulmonary shunt. Emergency therapy, especially for out-of-hospital treatment, can only consist of basic measures, which are discussed.

EMS defibrillation-first policy may not improve outcome in out-of-hospital cardiac arrest.

OBJECTIVE: Early defibrillation using automated external defibrillators (AEDs) has been advocated to improve survival in witnessed out-of-hospital cardiac arrest (OHCA) due to pulseless ventricular tachycardia (VT) and ventricular fibrillation (VF). However, when VT/VF is untreated and prolonged for more than a few minutes, defibrillation using AEDs may fail. METHODS: This retrospective study reviewed the charts from local emergency medical service (EMS) between the years 1993 to 2001 to evaluate the value of the AED after its introduction into our EMS. All witnessed OHCA due to VT/VF were analysed; cases of collapse witnessed by EMS were excluded. The primary endpoint was defined as survival to hospital discharge and at 1-year follow-up, and the secondary endpoint as survival without major neurological deficit. A total of 76 patients were treated for witnessed VT/VF before the implementation of the AED and 92 patients after its implementation. RESULTS: Before the introduction of paramedic AED defibrillation, physician defibrillation was performed at 15.6 min (+/-5.5, S.D.). After the introduction of AED defibrillation, paramedic defibrillation was performed at 5.7 min (+/-2.4, S.D.); the mean response interval from the call to defibrillation was shortened significantly (P<0.001). At the same time, survival to hospital discharge decreased from 23.7% (18/76 patients) to 14.1% (13/92) (P=0.112) and at 1-year follow-up from 17.1% (13/76) to 9.8% (9/92) (P=0.161). Favourable neurological outcome at 1-year follow-up also decreased from 14.5% (11/76) to 8.7% (8/92) (P=0.239). CONCLUSION: Implementation of the AED did not improve survival or a favourable neurological outcome in patients with OHCA due to VF/VT. However, with 5.7 min time to defibrillation, our EMS did not meet the criteria for early defibrillation. For prolonged periods of VT/VF, initial basic life support (BLS) may be superior to immediate AED. If response times of <4 min cannot be attained by the emergency systems, reconsidering of resuscitation algorithms seems to be advisable.