Markus Castegren

Single Deranged Physiologic Parameters Are Associated With Mortality in a Low-Income Country

Objective:To investigate whether deranged physiologic parameters at admission to an ICU in Tanzania are associated with in-hospital mortality and compare single deranged physiologic parameters to a more complex scoring system. Design:Prospective, observational cohort study of patient notes and admission records. Data were collected on vital signs at admission to the ICU, patient characteristics, and outcomes. Cutoffs for deranged physiologic parameters were defined a priori and their association with in-hospital mortality was analyzed using multivariable logistic regression. Setting:ICU at Muhimbili National Hospital, Dar es Salaam, Tanzania. Patients:All adults admitted to the ICU in a 15-month period. Measurements and Main Results:Two hundred sixty-nine patients were included: 54% female, median age 35 years. In-hospital mortality was 50%. At admission, 69% of patients had one or more deranged physiologic parameter. Sixty-four percent of the patients with a deranged physiologic parameter died in hospital compared with 18% without (p < 0.001). The presence of a deranged physiologic parameter was associated with mortality (adjusted odds ratio, 4.64; 95% CI, 1.95–11.09). Mortality increased with increasing number of deranged physiologic parameters (odds ratio per deranged physiologic parameter, 2.24 [1.53–3.26]). Every individual deranged physiologic parameter was associated with mortality with unadjusted odds ratios between 1.92 and 16.16. A National Early Warning Score of greater than or equal to 7 had an association with mortality (odds ratio, 2.51 [1.23–5.14]). Conclusion:Single deranged physiologic parameters at admission are associated with mortality in a critically ill population in a low-income country. As a measure of illness severity, single deranged physiologic parameters are as useful as a compound scoring system in this setting and could be termed “danger signs.” Danger signs may be suitable for the basis of routines to identify and treat critically ill patients.

Vital Signs Directed Therapy: Improving Care in an Intensive Care Unit in a Low-Income Country

Background Global Critical Care is attracting increasing attention. At several million deaths per year, the worldwide burden of critical illness is greater than generally appreciated. Low income countries (LICs) have a disproportionally greater share of critical illness, and yet critical care facilities are scarce in such settings. Routines utilizing abnormal vital signs to identify critical illness and trigger medical interventions have become common in high-income countries but have not been investigated in LICs. The aim of the study was to assess whether the introduction of a vital signs directed therapy protocol improved acute care and reduced mortality in an Intensive Care Unit (ICU) in Tanzania. Methods and Findings Prospective, before-and-after interventional study in the ICU of a university hospital in Tanzania. A context-appropriate protocol that defined danger levels of severely abnormal vital signs and stipulated acute treatment responses was implemented in a four week period using sensitisation, training, job aids, supervision and feedback. Acute treatment of danger signs at admission and during care in the ICU and in-hospital mortality were compared pre and post-implementation using regression models. Danger signs from 447 patients were included: 269 pre-implementation and 178 post-implementation. Acute treatment of danger signs was higher post-implementation (at admission: 72.9% vs 23.1%, p<0.001; in ICU: 16.6% vs 2.9%, p<0.001). A danger sign was five times more likely to be treated post-implementation (Prevalence Ratio (PR) 4.9 (2.9–8.3)). Intravenous fluids were given in response to 35.0% of hypotensive episodes post-implementation, as compared to 4.1% pre-implementation (PR 6.4 (2.5–16.2)). In patients admitted with hypotension, mortality was lower post-implementation (69.2% vs 92.3% p = 0.02) giving a numbers-needed-to-treat of 4.3. Overall in-hospital mortality rates were unchanged (49.4% vs 49.8%, p = 0.94). Conclusion The introduction of a vital signs directed therapy protocol improved the acute treatment of abnormal vital signs in an ICU in a low-income country. Mortality rates were reduced for patients with hypotension at admission but not for all patients.

Differences in Organ Dysfunction in Endotoxin Tolerant Pigs Under Intensive Care Exposed to a Second Hit of Endotoxin

ABSTRACT Endotoxin tolerance is a well-studied phenomenon associated with a reduced inflammatory response. In the switch from an inflammatory to an anti-inflammatory response in clinical sepsis, the concept of endotoxin tolerance is of obvious interest. However, only limited data exist regarding the effect of endotoxin tolerance on organ dysfunction, and therefore, this was investigated in a porcine intensive care sepsis model. Twenty-seven healthy pigs, including nine control animals, were included in the study. Twelve pigs pre-exposed to 24 h of intravenous endotoxin infusion and intensive care and six unexposed pigs were given either a high- or low-dose endotoxin challenge for 6 h. Inflammatory, circulatory, hypoperfusion, and organ dysfunction parameters were followed. The inflammatory responses as well as parameters representing circulation, hypoperfusion, and cardiac and renal function were all markedly attenuated in animals pre-exposed to endotoxin and intensive care as compared with animals not pre-exposed. In animals pre-exposed to endotoxin and given the high-dose of endotoxin challenge, deterioration in pulmonary function was equal to or even worse than in animals not pre-exposed. In contrast to the overall protective effect of endotoxin tolerance observed in other organ systems, the lungs of endotoxin-tolerant animals demonstrated an increased responsiveness to high-dose endotoxin challenge.

Endotoxin Tolerance Variation over 24 h during Porcine Endotoxemia: Association with Changes in Circulation and Organ Dysfunction

Endotoxin tolerance (ET), defined as reduced inflammatory responsiveness to endotoxin challenge following a first encounter with endotoxin, is an extensively studied phenomenon. Although reduced mortality and morbidity in the presence of ET has been demonstrated in animal studies, little is known about the temporal development of ET. Further, in acute respiratory distress syndrome ET correlates to the severity of the disease, suggesting a complicated relation between ET and organ dysfunction. Eighteen pigs were subjected to intensive care and a continuous endotoxin infusion for 24 h with the aim to study the time course of early ET and to relate ET to outcome in organ dysfunction. Three animals served as non-endotoxemic controls. Blood samples for cytokine analyses were taken and physiological variables registered every third hour. Production of TNF-α, IL-6, and IL-10 before and after endotoxin stimulation ex vivo was measured. The difference between cytokine values after and before ex vivo LPS stimulation (Δ-values) was calculated for all time points. ΔTNF-α was employed as the principal marker of ET and lower ΔTNF-α values were interpreted as higher levels of ET. During endotoxin infusion, there was suppression of ex vivo productions of TNF-α and IL-6 but not of IL-10 in comparison with that at 0 h. The ex vivo TNF-α values followed another time concentration curve than those in vivo. ΔTNF-α was at the lowest already at 6 h, followed by an increase during the ensuing hours. ΔTNF-α at 6 h correlated positively to blood pressure and systemic vascular resistance and negatively to cardiac index at 24 h. In this study a temporal variation of ET was demonstrated that did not follow changes in plasma TNF-α concentrations. Maximal ET occurred early in the course and the higher the ET, the more hyperdynamic the circulation 18 h later.

Beneficial Antimicrobial Effect of the Addition of an Aminoglycoside to a β-Lactam Antibiotic in an E. coli Porcine Intensive Care Severe Sepsis Model.

This study aimed to determine whether the addition of an aminoglycoside to a ß-lactam antibiotic increases the antimicrobial effect during the early phase of Gram-negative severe sepsis/septic shock. A porcine model was selected that considered each animal’s individual blood bactericidal capacity. Escherichia coli, susceptible to both antibiotics, was given to healthy pigs intravenously during 3 h. At 2 h, the animals were randomized to a 20-min infusion with either cefuroxime alone (n = 9), a combination of cefuroxime+tobramycin (n = 9), or saline (control, n = 9). Blood samples were collected hourly for cultures and quantitative polymerase chain reaction (PCR). Bacterial growth in the organs after 6 h was chosen as the primary endpoint. A blood sample was obtained at baseline before start of bacterial infusion for ex vivo investigation of the blood bactericidal capacity. At 1 h after the administration of the antibiotics, a second blood sample was taken for ex vivo investigation of the antibiotic-induced blood killing activity. All animals developed severe sepsis/septic shock. Blood cultures and PCR rapidly became negative after completed bacterial infusion. Antibiotic-induced blood killing activity was significantly greater in the combination group than in the cefuroxime group (p<0.001). Growth of bacteria in the spleen was reduced in the two antibiotic groups compared with the controls (p<0.01); no difference was noted between the two antibiotic groups. Bacterial growth in the liver was significantly less in the combination group than in the cefuroxime group (p<0.05). High blood bactericidal capacity at baseline was associated with decreased growth in the blood and spleen (p<0.05). The addition of tobramycin to cefuroxime results in increased antibiotic-induced blood killing activity and less bacteria in the liver than cefuroxime alone. Individual blood bactericidal capacity may have a significant effect on antimicrobial outcome.

Lung protective ventilation induces immunotolerance and nitric oxide metabolites in porcine experimental postoperative sepsis.

Low tidal volume ventilation is beneficial in patients with severe pulmonary dysfunction and would, in theory, reduce postoperative complications if implemented during routine surgery. The study aimed to investigate whether low tidal volume ventilation and high positive end-expiratory pressure (PEEP) in a large animal model of postoperative sepsis would attenuate the systemic inflammatory response and organ dysfunction. Thirty healthy pigs were randomized to three groups: Group Prot-7h, i.e. protective ventilation for 7 h, was ventilated with a tidal volume of 6 mL x kg-1 for 7 h; group Prot-5h, i.e. protective ventilation for 5 h, was ventilated with a tidal volume of 10 mL x kg-1 for 2 h, after which the group was ventilated with a tidal volume of 6 mL x kg-1; and a control group that was ventilated with a tidal volume of 10 mL x kg-1 for 7 h. In groups Prot-7h and Prot-5h PEEP was 5 cmH2O for 2 h and 10 cmH2O for 5 h. In the control group PEEP was 5 cmH2O for the entire experiment. After surgery for 2 h, postoperative sepsis was simulated with an endotoxin infusion for 5 h. Low tidal volume ventilation combined with higher PEEP led to lower levels of interleukin 6 and 10 in plasma, higher PaO2/FiO2, better preserved functional residual capacity and lower plasma troponin I as compared with animals ventilated with a medium high tidal volume and lower PEEP. The beneficial effects of protective ventilation were seen despite greater reductions in cardiac index and oxygen delivery index. In the immediate postoperative phase low VT ventilation with higher PEEP was associated with reduced ex vivo plasma capacity to produce TNF-α upon endotoxin stimulation and higher nitrite levels in urine. These findings might represent mechanistic explanations for the attenuation of systemic inflammation and inflammatory-induced organ dysfunction.

Fatal hemolytic uremic syndrome associated with day care surgery and anaesthesia: a case report.

BackgroundThrombotic angiopathies, i.e. haemolytic uremic syndrome and thrombotic thrombocytopenic purpura, are thought to occur in patients with a combination of risk factors (e.g., an infection with shiga-toxin-producing Escherichia coli (E. coli) or low activity of the metalloproteinase Adamts-13) and a pathophysiological trigger (e.g., anti-endothelial antibodies, cytokines or activation of chemokine receptor 4). To our knowledge, this is the first report describing an association between haemolytic uremic syndrome and routine surgery and anaesthesia.Case presentationWe present a case in which a 67-year-old Caucasian female developed fatal haemolytic uremic syndrome in the immediate postoperative period of uncomplicated day care surgery. The patient had suffered gastrointestinal symptoms followed by confusion approximately two weeks before surgery, but had been without any symptoms in the week before surgery. Haemolytic uremic syndrome with cerebral symptoms ranging from initial anxiety to subsequent seizures and coma developed within a few hours after the end of surgery. In addition, acute kidney failure and severe thrombocytopenia occurred about the same time. During intensive care, the patient was found to be positive for enterohaemorrhagic E. coli (EHEC) in faeces.ConclusionAnaesthesiologists should be notified that haemolytic uremic syndrome is an uncommon differential diagnosis in patients with postoperative seizures and coma. Patients with a recent enterohemmoragic E.Coli infection should be followed postoperatively for signs of haemolytic uremic syndrome.

Performance of plasma calprotectin as a biomarker of early sepsis: a pilot study

AIM To determine the performance of plasma calprotectin as a marker of sepsis on intensive care unit (ICU) admission and as a marker of mortality day 30 post-ICU admission. MATERIALS & METHODS Consecutive ICU patients were allocated to: sepsis (n = 15), postoperative inflammation (n = 23) and intoxication without inflammation (n = 7) groups. RESULTS Calprotectin was 4.3 (2.6-8.2; mg/l; median [interquartile range]) in the sepsis, 2.8 (1.6-4.4) in the postoperative and 0.7 (0.4-1.6) in the intoxication groups. Area under the receiver operating characteristic curve for sepsis versus intoxication group was: 0.95, for sepsis versus postoperative groups: 0.65 and for survivors versus nonsurvivors: 0.70. CONCLUSION Calprotectin was a sensitive marker of systemic inflammation, is a potential sepsis marker and performed well as mortality predictor in this pilot study.

Evaluating the effects of protective ventilation on organ-specific cytokine production in porcine experimental postoperative sepsis

BackgroundProtective ventilation with lower tidal volume (VT) and higher positive end-expiratory pressure (PEEP) reduces the negative additive effects of mechanical ventilation during systemic inflammatory response syndrome. We hypothesised that protective ventilation during surgery would affect the organ-specific immune response in an experimental animal model of endotoxin-induced sepsis-like syndrome.Methods30 pigs were laparotomised for 2 hours (h), after which a continuous endotoxin infusion was started at 0.25 micrograms × kg−1 × h−1 for 5 h. Catheters were placed in the carotid artery, hepatic vein, portal vein and jugular bulb. Animals were randomised to two protective ventilation groups (n = 10 each): one group was ventilated with VT 6 mL × kg−1 during the whole experiment while the other group was ventilated during the surgical phase with VT of 10 mL × kg−1. In both groups PEEP was 5 cmH2O during surgery and increased to 10 cmH2O at the start of endotoxin infusion. A control group (n = 10) was ventilated with VT of 10 mL × kg−1 and PEEP 5 cm H20 throughout the experiment. In four sample locations we a) simultaneously compared cytokine levels, b) studied the effect of protective ventilation initiated before and during endotoxemia and c) evaluated protective ventilation on organ-specific cytokine levels.ResultsTNF-alpha levels were highest in the hepatic vein, IL-6 levels highest in the artery and jugular bulb and IL-10 levels lowest in the artery. Protective ventilation initiated before and during endotoxemia did not differ in organ-specific cytokine levels. Protective ventilation led to lower levels of TNF-alpha in the hepatic vein compared with the control group, whereas no significant differences were seen in the artery, portal vein or jugular bulb.ConclusionsVariation between organs in cytokine output was observed during experimental sepsis. We see no implication from cytokine levels for initiating protective ventilation before endotoxemia. However, during endotoxemia protective ventilation attenuates hepatic inflammatory cytokine output contributing to a reduced total inflammatory burden.