Clinical and laboratory signs of haemophagocytic lymphohistiocytosis associated with pandemic influenza A (H1N1) infection in patients needing extracorporeal membrane oxygenation: A retrospective observational study.

BACKGROUND: Severe pandemic influenza has been associated with the hyperinflammatory condition secondary haemophagocytic lymphohistiocytosis (HLH). OBJECTIVES: To determine the frequency, degree, character and possible cause of influenza-associated HLH in critically ill patients with severe acute respiratory distress syndrome due to influenza A (H1N1) infection requiring extracorporeal membrane oxygenation (ECMO) support at our hospital. DESIGN: A retrospective observational study. PATIENTS AND SETTING: Medical data were retrieved retrospectively from 11 consenting patients of thirteen adults infected with pandemic influenza A (H1N1) 2009 requiring ECMO between July 2009 and January 2010 at the ECMO Centre of Karolinska University Hospital, Stockholm, Sweden. All patients were evaluated for HLH using HLH-2004 criteria and HScore. RESULTS: Eleven patients (median age 31 years) were included in the study and all survived. All patients showed signs of multiple organ dysfunction and pronounced inflammation, more severe in the four patients with HLH who had significantly higher peak serum concentrations of ferritin (P = 0.024), alkaline phosphatase (P = 0.012) and gamma-glutamyl transferase (P = 0.024), lower concentration of albumin (P = 0.0086) and more frequently hepatomegaly (P = 0.048). Abnormal lymphocyte cytotoxicity (lytic units <10) and a low proportion of natural killer (NK) cells were observed in three of four patients with HLH. Notably, we found a significant inverse correlation between serum ferritin concentration and NK cell and cytotoxic T lymphocyte percentages (rs = -0.74, P = 0.0013 and rs = -0.79, P = 0.0025, respectively). One HLH patient received HLH-directed cytotoxic therapy, another intravenous immunoglobulin and the other two no specific HLH-directed therapy. CONCLUSION: Critically ill patients, including healthy young adults, with pandemic influenza may develop HLH and should be monitored for signs of hyperinflammation and increasing organ dysfunction, and evaluated promptly for HLH because HLH-directed therapy may then be beneficial. The association of low NK percentages with hyperferritinaemia may suggest a role for reduced NK cell numbers, possibly also cytotoxic T lymphocytes, and subsequently reduced lymphocyte cytotoxicity, in the pathogenesis of hyperinflammation and secondary HLH.

Does extracorporeal membrane oxygenation attenuate hypoxic pulmonary vasoconstriction in a porcine model of global alveolar hypoxia?

BACKGROUND: During severe respiratory failure, hypoxic pulmonary vasoconstriction (HPV) is partly suppressed, but may still play a role in increasing pulmonary vascular resistance (PVR). Experimental studies suggest that the degree of HPV during severe respiratory failure is dependent on pulmonary oxygen tension (PvO2 ). Therefore, it has been suggested that increasing PvO2 by veno-venous extracorporeal membrane oxygenation (V-V ECMO) would adequately reduce PVR in V-V ECMO patients. OBJECTIVE: Whether increased PvO2 by V-V ECMO decreases PVR in global alveolar hypoxia. METHODS: Nine landrace pigs were ventilated with a mixture of oxygen and nitrogen. After 15 minutes of stable ventilation and hemodynamics, the animals were cannulated for V-V ECMO. Starting with alveolar normoxia, the fraction of inspiratory oxygen (FI O2 ) was stepwise reduced to establish different degrees of alveolar hypoxia. PvO2 was increased by V-V ECMO. RESULTS: V-V ECMO decreased PVR (from 5.5 [4.5-7.1] to 3.4 [2.6-3.9] mm Hg L-1  min, P = .006) (median (interquartile range),) during ventilation with FI O2 of 0.15. At lower FI O2 , PVR increased; at FI O2 0.10 to 4.9 [4.2-7.0], P = .036, at FI O2 0.05 to 6.0 [4.3-8.6], P = .002, and at FI O2 0 to 5.4 [3.5 - 7.0] mm Hg L-1  min, P = .05. CONCLUSIONS: The effect of increased PvO2 by V-V ECMO on PVR depended highly on the degree of alveolar hypoxia. Our results partly explain why V-V ECMO does not always reduce right ventricular afterload at severe alveolar hypoxia.

Long-term pulmonary function and quality of life in adults after extracorporeal membrane oxygenation for respiratory failure.

BACKGROUND: There is a significant long-term burden on survivors after acute respiratory distress syndrome, even 5 years after discharge. This is not well investigated in patients treated with extracorporeal membrane oxygenation. The objective of this study was to describe very-long-term (⩾3 years) disability in lung function and morphology, quality of life, mood disorders, walking capacity, and return to work status in extracorporeal membrane oxygenation survivors. METHODS: Single-center retrospective cohort study on long-term survivors treated with extracorporeal membrane oxygenation for respiratory failure between 1995 and 2010 at a tertiary referral center in Sweden. Eligible patients were approached, and those who consented were interviewed and investigated during a day at the hospital. RESULTS: A total of 38 patients were investigated with a median follow-up time of 9.0 years. Quality of life was reduced in several Short form 36 (SF-36) subscales and all domains of the St George's Respiratory Questionnaire, similar to previous studies in conventionally managed acute respiratory distress syndrome survivors. A reduced diffusion capacity of carbon monoxide was seen in 47% of patients, and some degree of residual lung parenchymal pathology was seen in 82%. Parenchymal pathology correlated with reductions in quality of life and diffusion capacity. Symptoms of anxiety and depression were seen in 22% and 14%, respectively. CONCLUSION: A significant long-term burden remains even 3-17 years after extracorporeal membrane oxygenation treatment, similar to conventionally managed acute respiratory distress syndrome survivors. Future prospective studies are needed to elucidate risk factors for these sequelae.

Long-Term Cognitive Outcome and Brain Imaging in Adults After Extracorporeal Membrane Oxygenation.

OBJECTIVES: To investigate the presence of cognitive dysfunction and brain lesions in long-term survivors after treatment with extracorporeal membrane oxygenation for severe respiratory failure, and to see whether patients with prolonged hypoxemia were at increased risk. DESIGN: A single-center retrospective cohort study. SETTING: Tertiary referral center for extracorporeal membrane oxygenation in Sweden. PATIENTS: Long-term survivors treated between 1995 and July 2009. Seven patients from a previously published study investigated with a similar protocol were included. INTERVENTIONS: Brain imaging, neurocognitive testing, interview. MEASUREMENTS AND MAIN RESULTS: Thirty-eight patients (i.e., n = 31 + 7) were enrolled and investigated in median 9.0 years after discharge. Only memory tests were performed in 10 patients, mainly due to a lack of formal education necessary for the test results to be reliable. Median full-scale intelligence quotient, memory index, and executive index were 97, 101, and 104, respectively (normal, 100 ± 15). Cognitive function was not reduced in the group with prolonged hypoxemia. Brain imaging showed cerebrovascular lesions in 14 of 38 patients (37%), most commonly in the group treated with venoarterial extracorporeal membrane oxygenation (7/11, 64%). In this group, memory function and executive function were significantly reduced. CONCLUSIONS: Patients treated with extracorporeal membrane oxygenation for respiratory failure may have normal cognitive function years after treatment, if not affected by cerebrovascular lesions. Permissive hypoxemia was not correlated with long-term cognitive dysfunction in the present study. Further prospective studies with minimal loss to follow-up are direly needed to confirm our findings.

[Tetanus, an almost forgotten but serious disease]. / Tetanus ­ nästan bortglömd men allvarlig sjukdom - Äldre kvinnor är en riskgrupp, diagnosen kan vara en utmaning.

Tetanus, an almost forgotten but serious disease Tetanus is the systemic consequence of a local infection with Clostridium tetani, that produces toxin which spreads in the systemic circulation. In developed countries, it is extremely rare. Women born before 1950 are a group at risk due to lower prevalence of immunisation. This report describes a case of tetanus. The patient is a previously healthy 82-year-old woman. She presented to primary care with a complaint of stiffness in the neck and jaw. A physical exam and basic laboratory tests were normal apart from a slightly increased blood pressure. Later the same day she was admitted to the intensive care unit for suspected tetanus. During the night she deteriorated with marked stiffness in her thorax and, as a result of this, severe respiratory distress. After induction of anesthesia she was ventilated and intubated without problem. The treatment for tetanus, an antibody, was given 5 hours later after urgent delivery from the national supply. The patient was successfully weaned from the ventilator after 37 days. During intensive care she had fluctuating stiffness and autonomic instability, both commonly described in patients with tetanus.

Does permissive hypoxaemia during extracorporeal membrane oxygenation cause long-term neurological impairment?: A study in patients with H1N1-induced severe respiratory failure.

BACKGROUND: The Extracorporeal Life Support Organisation accepts permissive hypoxaemia in adult patients during extracorporeal membrane oxygenation (ECMO). The neurological long-term outcome of this approach has not yet been studied. OBJECTIVES: We investigated the prevalence of brain lesions and cognitive dysfunction in survivors from the Influenza A/H1N1 2009 pandemic treated with permissive hypoxaemia during ECMO for severe acute respiratory distress syndrome (ARDS). Our hypothesis was that this method is reasonable if tissue hypoxia is avoided. DESIGN: Long-term follow-up study after ECMO. SETTING: Karolinska University Hospital, Sweden, from October 2012 to July 2013. PATIENTS: Seven patients treated with ECMO for severe influenza A/H1N1-induced ARDS were studied 3.2 years after treatment. Blood lactate concentrations were used as a surrogate for tissue oxygenation. INTERVENTIONS: Neurocognitive outcome was studied with standardised cognitive tests and MRI of the brain. MAIN OUTCOME MEASURES: Cognitive functioning and hypoxic brain lesions after permissive hypoxaemia during ECMO. The observation period was the first 10 days of ECMO or the entire treatment period if shorter than 10 days. RESULTS: Eleven of 13 patients were still alive 3 years after ECMO. We were able to contact seven of these patients (mean age 31 years), who all agreed to participate in this study. Mean ±â€ŠSD peripherally measured arterial saturation during the observation period was 79 ±â€Š10%. Full-scale Intelligence Quotient was within one standard deviation or above from the mean of a healthy population in five patients, and was 1.5 SD below the mean in one patient. In one other patient, it could not be determined because of a lack of formal education. Memory functioning was normal in all patients. MRI showed no changes related to cerebral hypoxia. CONCLUSIONS: Permissive hypoxaemia during ECMO might not negatively affect long-term cognitive outcome if adequate organ perfusion is maintained. TRIAL REGISTRATION: at Clinicaltrials.gov NCT01763060.

Autologous Peripheral Blood Mononuclear Cells as Treatment in Refractory Acute Respiratory Distress Syndrome.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a devastating disorder. Despite enormous efforts in clinical research, effective treatment options are lacking, and mortality rates remain unacceptably high. OBJECTIVES: A male patient with severe ARDS showed no clinical improvement with conventional therapies. Hence, an emergent experimental intervention was performed. METHODS: We performed intratracheal administration of autologous peripheral blood-derived mononuclear cells (PBMCs) and erythropoietin (EPO). RESULTS: We found that after 2 days of initial PBMC/EPO application, lung function improved and extracorporeal membrane oxygenation (ECMO) support was reduced. Bronchoscopy and serum inflammatory markers revealed reduced inflammation. Additionally, serum concentration of miR-449a, b, c and miR-34a, a transient upregulation of E-cadherin and associated chromatin marks in PBMCs indicated airway epithelial differentiation. Extracellular vesicles from PBMCs demonstrated anti-inflammatory capacity in a TNF-α-mediated nuclear factor-x03BA;B in vitro assay. Despite improving respiratory function, the patient died of multisystem organ failure on day 38 of ECMO treatment. CONCLUSIONS: This case report provides initial encouraging evidence to use locally instilled PBMC/EPO for treatment of severe refractory ARDS. The observed clinical improvement may partially be due to the anti-inflammatory effects of PBMC/EPO to promote tissue regeneration. Further studies are needed for more in-depth understanding of the underlying mechanisms of in vivo regeneration.

The Stockholm experience: interhospital transports on extracorporeal membrane oxygenation.

INTRODUCTION: In severe respiratory and/or circulatory failure, extracorporeal membrane oxygenation (ECMO) may be a lifesaving procedure. Specialized departments provide ECMO, and these patients often have to be transferred for treatment. Conventional transportation is hazardous, and deaths have been described. Only a few centers have performed more than 100 ECMO transports. To date, our mobile ECMO teams have performed more than 700 transports with patients on ECMO since 1996. We describe 4 consecutive years (2010-2013) of 322 national and international ECMO transports and report adverse events. METHODS: Data were retrieved from our local databases. Neonatal, pediatric and adult patients were transported, predominantly with refractory severe respiratory failure. RESULTS: The patients were cannulated in 282 of the transports, and ECMO was started in these patients at the referring hospital and then they were transported to our ECMO intensive care unit. In 40 cases, the patient was already on ECMO. Of the transports, 60% were by aircraft, and the distances varied from 6.9 to 13,447 km. In about 27.3% of the transports, adverse events occurred. Of these, the most common were either patient-related (22%) or equipment-related (5.3%). No deaths occurred during transport, and transferred patients exhibited the same mortality rate as in-hospital patients. CONCLUSIONS: Long- and short-distance interhospital transports on ECMO can be safely performed. A myriad of complications can occur, but the mortality risk is very low. The staff involved should be highly competent in intensive care, ECMO physiology and physics, cannulation, intensive care transport and air transport medicine. They should also be skilled in recognition of risk factors involved in these patients.

Predicting mortality risk in patients undergoing venovenous ECMO for ARDS due to influenza A (H1N1) pneumonia: the ECMOnet score.

PURPOSE: The decision to start venovenous extracorporeal membrane oxygenation (VV ECMO) is commonly based on the severity of respiratory failure, with little consideration of the extrapulmonary organ function. The aim of the study was to identify predictors of mortality and to develop a score allowing a better stratification of patients at the time of VV ECMO initiation. METHODS: This was a prospective multicenter cohort study on 60 patients with influenza A (H1N1)-associated respiratory distress syndrome participating in the Italian ECMOnet data set in the 2009 pandemic. Criteria for ECMO institution were standardized according to national guidelines. RESULTS: The survival rate in patients treated with ECMO was 68 %. Significant predictors of death before ECMO institution by multivariate analysis were hospital length of stay before ECMO institution (OR = 1.52, 95 % CI 1.12-2.07, p = 0.008); bilirubin (OR = 2.32, 95 % CI 1.52-3.52, p < 0.001), creatinine (OR = 7.38, 95 % CI 1.43-38.11, p = 0.02) and hematocrit values (OR = 0.82, 95 % CI 0.72-0.94, p = 0.006); and mean arterial pressure (OR = 0.92, 95 % CI 0.88-0.97, p < 0.001). The ECMOnet score was developed based on these variables, with a score of 4.5 being the most appropriate cutoff for mortality risk prediction. The high accuracy of the ECMOnet score was further confirmed by ROC analysis (c = 0.857, 95 % CI 0.754-0.959, p < 0.001) and by an independent external validation analysis (c = 0.694, 95 % CI 0.562-0.826, p = 0.004). CONCLUSIONS: Mortality risk for patients receiving VV ECMO is correlated to the extrapulmonary organ function at the time of ECMO initiation. The ECMOnet score is a tool for the evaluation of the appropriateness and timing of VV ECMO in acute lung failure.

Local lactate and histamine changes in small bowel circulation measured by microdialysis in pig hemorrhagic shock.

Hemorrhagic shock results in inadequate tissue oxygenation. Plasma lactate (L) can characterize the degree of systemic oxygen debt (OD), but gives no information on local changes. The aim of this study was to characterize different degrees of hemorrhagic shock by microdialysis measurement of L and histamine (H) in small bowel circulation. Thirty-eight pigs were randomized to five groups of increasing OD (< 50 --> 120 ml/kg). The OD was accrued by hemorrhage over 60 min and was followed by retransfusion and observation for 3 days. In parallel to plasma probes, subserosa(ss)-, submucosa(sm)-, and intraluminal(il)-L- and H-probes were obtained by small bowel microdialysis every 30 min for 210 min. Ss- and sm-L increased during hemorrhage from 1.2 +/- 0.06 and 1.18 +/- 0.06 to 2.57 +/- 0.15 and 2.96 +/- 0.27 mmol/L. Highest mean L > 3.5mmol/L resulted 90 and 120 min after induction of hemorrhage. Although ss- and sm- levels hardly differed, il-L was significantly decreased with 0.27 +/- 0.02 mmol/L at 0 min and highest mean il-L at 120 min: 2.45 +/- 0.51 mmol/L. Sm-L was significantly increased after 60, 90, 120, and 150 min of highest hemorrhage severity (OD > 100 mL/kg). In parallel, systemic L increased significantly during hemorrhage and correlated well with the severity of shock. Although systemic H increased significantly during hemorrhage (from 1.3 +/- 0.31 to 15.2 +/- 0.67 ng/mL), H-dialysates showed no effect either over time nor with the degree of hemorrhage. In conclusion, microdialysis allows evaluation of local L changes in small bowel circulation in pig hemorrhagic shock. Sm-L levels appear to correlate with the degree of shock. Local H changes were not observed during hemorrhagic shock in this study.