Uid Resuscitation Research Articles

FLUID THERAPY IN MECHANICALLY VENTILATED CRITICALLY ILL CHILDREN: THE SODIUM, CHLORIDE AND WATER BURDEN OF FLUID CREEP”

Aim: To quantify the burden of sodium, chloride and water in uid creep among critically ill mechanically ventilated children. All critically ill children between1year to 15 years of age on mec Method: hanical ventilation admitted in PICU were included in the study. The cause for PICU admission will be categorized into respiratory failure, sepsis and neurological disease. The amount of resuscitation, replacement, and maintenance uid will be calculated. Maintenance uid calculated by Holliday—Segar formula, in addition measure the amount of sodium, chloride and water in infusions, transfusions, vehicle for drug administration and ush. The major source Result: of water input was uid creep followed by uid maintenance. The quantitative role of uid boluses/uid resuscitation was minor and quantitatively similar to blood components. Fluid creep represented the major source of sodium and chloride followed by maintenance uids, resuscitation uid and blood components, Fluid creep is quantitatively the most Conclusion: relevant uid in the PICU and future research and clinical efforts should address this topic in order to improve the quality of care of critically ill children

TO STUDY OUTCOME OF FLUID BOLUS IN MECHANICALLY VENTILATED CRITICALLY ILL CHILDREN

Introduction: In paediatric intensive care medicine, proper uid management in critically sick children who are mechanically ventilated continues to be a signicant issue and a hotly debated subject. However, there is currently no global agreement on uid management or removal techniques. A growing body of research demonstrates that excessive uid administration to critically ill patients beyond the resuscitation period is linked to negative outcomes. This study was done to assess the sodium and bicarbonate Objectives: levels in mechanically ventilated critically ill children and the effect of normal saline uid resuscitation. This is a retrospect Materials And Methods: ive study done in the PICU of a tertiary care centre. A total of 10 children admitted who required ventilation and uid resuscitation were studied. Many of the admitted children had Results: electrolyte imbalance at admission. The existence of electrolyte imbalance at admission, however, is the best predictor of mortality because such abnormalities aggravate the course of illness, regardless of the fundamental disease process. Regardless of the original illness Conclusion: process, the presence of electrolyte imbalance at the time of admission is a key prognostic signal in critically unwell children and has to be quickly treated as it may actively affect the child's fate and length of hospital stay.

A STUDY ON IMPROVED PATIENT OUTCOMES IN SEPTIC SHOCK WITH USE OF HYDROCORTIS

Management of sepsis is a time critical procedure; the consequences of improperly managed sepsis and septic shock can cause multiple organ dysfunction and death. The aim of this study was to evaluate of the role of hydrocortisone. Ÿ Sepsis is dened as life-threatening condition causing multi-organ dysfunction by a dysregulated host response to infection. Septic shock is a subset of sepsis with circulatory and cellular or metabolic dysfunction associated with a higher risk of mortality . Ÿ Sepsis is said to effect the hypothalamic pituitary adrenal axis, causing a relative adrenal insufficiency resulting in cardiovascular instability,metabolic disorders,and a sustained pro- inammatory state. Ÿ The role of pro-inammatory pathways suggests a potential use for corticosteroids as an adjuvant therapy in the treatment of sepsis and septic shock .The Surviving Sepsis campaign guidelines recommend that if adequate uid resuscitation and vasopressors have not restored the hemodynamic stability,it was postulated in limited data to use inj hydrocortisone 100mg i/v 8 hourly for 7 days . Ÿ There was an improvement in the overall survival and reduction in the mortality and morbidity of patients, as observed by early weaning off from vasopressor support,reduction in total leucocyte counts

A PROSPECTIVE LONGITUDINAL OBSERVATIONAL STUDY ON ACUTE PANCREATITIS: FACTORS INFLUENCING MORBIDITY AND MORTALITY

Background: Acute pancreatitis presents a broad clinical spectrum ranging from cases so mild that symptoms abate before the diagnosis is actively pursued, to cases which progress rapidly to multisystem failure and eventual demise of patient despite current mode of therapy. Aims And Objectives: To determine factors related to disease severity, mortality and morbidity in acute pancreatitis. Materials And Methods: Study design: A prospective longitudinal observational study. Study area: Ramakrishna Mission Seva Pratishthan Hospital, Kolkata. Study period: April 2017 to March 2018 Sample size: 76 patients diagnosed with acute pancreatitis after admission. All patients were subjected to a thorough history taking, clinical examination, routine blood tests and imaging and monitoring of vitals. Patients with complications like sepsis, shock or organ failure was treated in ICU, with invasive and non-invasive monitoring. Thorough IV uid resuscitation and appropriate analgesics were used with conservative management. Initially put in NPM, started with enteral feeding when ileus subsided or parenteral feeding at appropriate time if clinically unstable. ERCP was done followed by open/laparoscopic cholecystectomy in gallstone pancreatitis patients. Results: The overall mortality for the study group was 11.8 % and the morbidity rate was 31.5 %. The mortality for male was greater than that for female. The mortality for patients over 50 years of age was greater than that of patients below 50 years of age. The mean duration of hospitalization for the total study group was 14 days and it was found to be higher in male (18 days) than for female (10 days). The mortality for this idiopathic group(n=4, 16.67%) was found to be higher than that for the alcoholic group(n=3, 13.6%) and those with biliary tract disease(n=2, 6.67%), whereas morbidity of the alcoholic group(n=12, 40%) was found higher than the idiopathic group(n=8, 33.3%) and biliary disease group(n=4, 18.1%). Mortality rate in patients with pseudocyst was 10%, 50% in pancreatic abscess, 42.8% in circulatory failure patients, 50% in renal failure patients and 75% in respiratory failure patients. Conclusion: Despite earlier recognition and appropriate care the morbidity and mortality rates have remained quite high in cases of severe attack of acute pancreatitis

A STUDY OF INFERIOR VENA CAVA AND RIGHT VENTRICLE DIAMETER IN ASSESSMENT OF VOLUME STATUS USING ULTRASONOGRAPHY IN EMERGENCY DEPARTMENT OF A TERITIARY CARE TEACHING HOSPITAL

INTRODUCTION: Physical examination ndings, vital signs, and laboratory results are other parameters used to estimate the intravascular volume status. These parameters are not reliable because they are inuenced by various clinical conditions.Some of these parameters may be found normal as the compensatory mechanisms of the body initiate; thus, this may result in delays in the detection of volume loss. The study was conducted in 50 patients and 50 control METHODOLOGY: s who visited the Emergency Department. Diameter of the IVC in expiration was lesser in the pre-uid re RESULTS: suscitation with a mean of 1.15 compared to the 1.52 in the post-uid resuscitation group. dIVCi – diameter of the IVC in inspiration was lesser in the pre-uid resuscitation with a mean of 0.81 compared to the 1.81 in the post-uid resuscitation group. IVC CI – IVC caval index was CONCLUSION: more in the pre-uid resuscitation with a mean of 33.42 compared to the 16.74 in the post-uid resuscitation group. dRV – diameter of the right ventricle was lesser in the pre-uid resuscitation with a mean of 2.80 compared to the 3.14 in the post-uid resuscitation group.

HEMODYNAMIC CHANGES IN PATIENTS TREATED FOR HYPOVOLEMIA

INTRODUCTION: Traumatic causes can result from penetrating and blunt trauma. Common traumatic injuries that can result in hemorrhagic shock include the following: myocardial laceration and rupture, major vessel laceration, solid abdominal organ injury, pelvic and femoral fractures, and scalp lacerations. Every individual in the world is at risk for traumatic injury. METHODOLOGY:The study was conducted in 50 patients and 50 controls who visited the Emergency Department. This is a prospective comparative study conducted in the adult Emergency Department. Heart rate w RESULTS: as more in the pre-uid resuscitation with a mean of 114.40 compared to the 100.30 in the post-uid resuscitation group Systolic blood pressure wa CONCLUSION: s lesser in the pre-uid resuscitation with a mean of 76.84 compared to the 101.08 in the post-uid resuscitation group

Citokin vihar és kezelése kritikus állapotú betegeknél

Az utóbbi évtizedekben a szepszis/szeptikus sokk előfordulása világszerte megnőtt, és mivel a kórházi halálozás egyik legmeghatározóbb oka, így kiemelt gazdasági és egészségügyi jelentőséggel bír. Terápiájában a kórkép korai felismerése és az ezzel megkezdett adekvát folyadékreszuszcitáció, valamint szervtámogató- és antimikrobiális kezelések és infekciókontroll ellenére a halálozási arány továbbra is magas (20-50% a vizsgált populációtól függően). A halálozás csökkentésére irányuló kutatások egyik legígéretesebb területe az immunrendszer és ezzel együtt a gazdaszervezet fertőzésre adott válaszának modulációja, melyek közül a vértisztító eljárások tűnnek az egyik legígéretesebb módszernek. A szeptikus sokk korai szakaszában a szervezet fertőzésre adott diszregulált immunválasza következtében kialakuló „citokinvihar” mélyebb megértése és a megfelelő pontokon történő módosítása hozzájárulhat az infl ammatorikus-antiinflammatorikus rendszer közötti egyensúly helyreállításához. Jelen közlemény célja, az ezzel kapcsolatos ismeretek rövid összefoglalása.

A Double-Blind, Randomized Control Trial of Rapidly Infused High Strong Ion Difference (SID) Fluid Versus Hartmann's Solution on Acid-Base Status in Sepsis Patients in the Emergency Department.

Balanced fluids are preferred in initial resuscitation of septic patients based on several recent studies. The Stewart's concept on acid-base balance predicts that high strong ion difference (SID) fluid thus will increase the pH level. To date, the impact of high SID fluid in septic patient with metabolic acidosis remains uncertain. We conducted single center, randomized, double-blind trial to compare the effect of high SID fluid vs. Hartmann's solution on acid-base status in selected sepsis patients in the Emergency Department. Septic patient with hyperlactatemia and metabolic acidosis were randomized to receive either high SID fl uid or Hartmann's solution during initial fl uid resuscitation. The primary outcome measures the pH and bicarbonate levels difference pre- and post- resuscitation. One hundred and sixty-two patients underwent randomization, 81 were assigned each to receive high SID fluid or Hartmann's solution. Both groups had similar baseline characteristics. High SID group received 23.5 mL/kg and the Hartmann's group received 22.7 mL/kg (p = 0.360). High SID fluid increased the mean (± SD) pH by 0.107 (± 0.09) vs. Hartmann's solution by 0.014 (± 0.12), p ≤ 0.001. Mean bicarbonate level increased signifi cantly in high SID group compared to Hartmann's (4.30 ± 3.76 vs. 1.25 ± 3.33, p ≤ 0.001). High SID group had higher post resuscitation lactate clearance than Hartmann's group (25.4 ± 28.3% vs. 12.0 ± 34.1%, p = 0.009). Shorter hospital stay was observed in highSID group 8.04 ± 5.96 days vs. Hartmann's group 12.18 ± 12.41 days (p = 0.048). Both groups showed no difference in incidence of pulmonary oedema, acute kidney injury and mortality. Initial resuscitation using high SID fluid in selected septic patient improves pH and bicarbonate levels. The high SID group had better post resuscitation lactate clearance and shorter hospital stay.

KNOWLEDGE OF MEDICAL RESCUE PERSONNEL REGARDING ADVANCED RESUSCITATION PROCEDURES IN CHILDREN

BACKGROUND: The purpose of this study is to attempt to evaluate the knowledge of medical rescue personnel within the scope of advanced resuscitation procedures in children. MATERIALS AND METHOD: We conducted a quantitative survey. The study included a group of 482 medical per- sonnel. The knowledge of medical staff was assessed by their correct answers to the survey questions. RESULTS: Especially among nurses, there was insuf cient knowledge of the following issues: determination of the child’s body weight (32–62%), the second dose of amiodarone during resuscitation of the child (42–90%), the volume of uids used during uid resuscitation (47–100%). CONCLUSIONS: Among studied groups, nurses are the worst prepared for conducting resuscitation in children. Nurses presented a low level of knowledge within the scope of advanced resuscitation procedures in children.

Target blood pressure in sepsis: between a rock and a hard place

We acknowledge the constructive comments of Beloncle and colleagues [1] regarding our recently published study. We demonstrated that targeting a mean arterial blood pressure (MAP) between 50 and 60 mmHg (Low-MAP) in porcine fecal peritonitis was associated with increased incidence of acute kidney injury (AKI) in comparison to targeting a MAP between 75 and 85 mmHg (High-MAP), which resulted in increased net positive fl uid balance and vasopressor load [2]. Beloncle and colleagues argue that a dilution eff ect of the higher amount of fl uid resuscitation on creatinine concentrations cannot be ruled out. Nevertheless, we report total hemoglobin concentrations in our manuscript [1], and, at study end, they were actually higher in animals in the High-MAP group than in the Low-MAP group (10.0 g/dl versus 8.4 g/dl, respectively, P = 0.008; Table 3 in the original manuscript). � e assumption that the low incidence of AKI in animals allocated to the High-MAP group could be explained by a dilution eff ect is, therefore, unlikely [2]. We hypothesize that the circulating blood volume in the High-MAP group was lower at study end as a consequence of norepinephrineinduced vasoconstriction. Moreover, Beloncle and colleagues suspect that low baseline hemoglobin levels in the Low-MAP group may have contributed to the development of kidney dysfunction [2]. Nevertheless, since the values were virtually identical in the Low- and High-MAP groups (9.3 mg/dl and 9.2 mg/dl, respectively), it seems unlikely that low hemoglobin levels - which were normal for young pigs explain the observed diff erences in AKI. Abbreviations AKI, acute kidney injury; MAP, mean arterial blood pressure.

Assessment of hemodynamic efficacy and safety of 6% hydroxyethyl starch 130/0.4 vs. 0.9% NaCl fluid replacement in patients with severe sepsis: how to guide fluid therapy?

We argue that assessing the hemodynamic effi cacy of hydroxyethyl starch (HES) versus NaCl in patients with severe sepsis requires an algorithm to direct the timing and amount of fl uid resuscitation. Such an algorithm may include hemodynamic fl ow parameters. In a recent issue of Critical Care, Guidet and colleagues [1] reported that a smaller amount of 6% HES 130/0.4 versus 0.9% NaCl was required to achieve hemodynamic stability (HDS) during the initial phase of fl uid resuscitation in patients with severe sepsis. Th e target parameters indicating HDS included central venous pressure (CVP) (8 to 12 mm Hg), a poor indicator of fl uid responsiveness [2], and a large urine output (>2 mL/kg per hour), and therefore pose a risk of over-infusion. Other authors have reported that over-infusion, elevated CVP, and excessive fl uid resuscitation with HES are associated with increased mortality in patients with sepsis [3,4]. In contrast, after initial HDS was achieved, no such target parameters were defi ned, and so the cumulative volumes of study drug infused over the course of four consecutive days in the intensive care unit (ICU) were similar for the HES (2,615 mL) and NaCl (2,788 mL) groups. No diff erences in mortality, hospital length of stay, or kidney function were found. Th is study may be showing only that, in the absence of an algorithm to guide fl uid resuscitation, intensivists use an unvarying amount of fl uids, but it is impossible to know whether these fl uids were, in fact, indicated. In patients undergoing major abdominal surgery, hemodynamic algorithms that guide the timing and amount of fl uid administration have helped determine the clinical effi cacy of fl uid therapy [5]. Th e negative results reported by Guidet and colleagues suggest that hemodynamic algorithms for patients with sepsis are urgently required to accurately compare the hemodynamic effi cacy, safety, and outcome of HES versus NaCl fl uid replacement.

Intractable hypotension and myocardial ischaemia induced by co-ingestion of ethanol and disulfiram

We report a case of a 42-year-old woman who presented with intractable hypotension and non-ST-elevation myocardial infarction as a result of a disulfi ram-ethanol reaction. During hypotension and ischaemic ECG changes we assessed cardiac function by echocardiography. Aggressive intravenous fl uid resuscitation was unsuccessful. Only after starting intravenous norepinephrine, blood pressure and ECG normalized. Coronary angiography performed three days after admission was normal. Cardiovascular adverse events are a known, potentially fatal complication of concomitant ingestion of ethanol and disulfi ram, but only few cases are reported in literature. Cardiologists and emergency care physicians should be aware of this interaction when a patient with chronic alcohol abuse presents with severe hypotension or myocardial ischaemia.

Sudden shock from capillary leak

In March, 2008, a 6-year-old girl was admitted to our paediatric intensive care unit with asthenia, disturbed consciousness, tachycardia, severe hypotension (50/30 mm Hg), and polycythaemia (haemoglobin 199 g/L). She had had a 6-day history of fever, but no evidence of haemorrhage or dehydration from diarrhoea which is a common cause of acute hypovolaemia in children. Past family and medical histories were unremark able. Lumbar tap showed no abnormalities but blood tests confi rmed polycythaemia (haemoglobin 189 g/L). Circulatory collapse and respira tory failure developed rapidly, although initial investi gations had exclu ded cardiogenic and septic shock and showed rhabdo myolysis (creatine kinase 4127 IU/L), myoglobinuria, mild hypoalbuminaemia (albumin 29 g/L, normal 35–50), and no infl ammatory markers. Myocardial stunning was seen on echocardiography. Invasive haemodynamic monitoring (PiCCO2, Pulsion Medical Systems, Munich, Germany) showed a cardiac index of 2·0 L min1 m2 (normal 3·3–5·5); troponin T concentration peaked at 0·11 μg/L (<0·03), and initial signs of kidney injury were seen. Our patient was managed with aggressive intravenous fl uid resuscitation (<3000 mL/m2 isotonic volume expander) and respiratory support. Vasoactive agents, dobutamine (5–10 μg kg1 min1) and fenoldopam (0·1 μg kg1 min1), were needed to stabilise blood pressure and urinary output, respectively. Immunoglobulin concentrations were within normal limits; she had no Bence-Jones proteinuria, and no antibodies to nuclear antigens, phospholipids, Scl70, or Jo-1. Serum creatine kinase concentration was consistently above 4000 IU/L. After fl uid loading under haemodynamic monitoring, the ejection fraction and cardiac index were normal on day 2, but our patient developed massive muscle oedema mainly of the legs, buttocks, and face, and pulmonary oedema (fi gure A, B), for which helmet-delivered non-invasive ventilation

Potential for overuse of corticosteroids and vasopressin in septic shock

Guidelines recommend corticosteroids and vasopressin to treat septic shock as per specifi c indications [1]. However, the results from trials evaluating both drugs confl ict. For corticosteroids, the 2002 Annane and colleagues study showed a survival benefi t for hydrocortisone/fl udro cortisone treatment in patients with an inappropriate cortisol response to a high-dose adrenocorticotropic hormone (ACTH) test [2], while the Corticosteroid Th erapy of Septic Shock (CORTICUS) trial found no diff erence in survival by patients’ response to ACTH [3]. Th e Vasopressin and Septic Shock Trial (VASST) demon strated a survival benefi t in less severe septic shock, but guidelines espouse use ‘in patients refractory to other vasopressors’ [1,4]. Clinical variability, leading to over treatment, may have negative eff ects on survival. To evaluate the impact of these evi dence limitations, we surveyed physicians in the Critical Illness Outcomes Study (CIOS). We developed a 15-item, self-administered survey to charac terize physician practice patterns for use of corticosteroids and vasopressin in septic shock. Th e survey, conducted anonymously and with implied consent, was distributed to 92 members of the CIOS listserv. Recipients were encouraged to solicit survey completion by their colleagues. CIOS is a multicenter study among 68 ICUs designed to determine whether ICU-based organi zational and structural factors are associated with patientrelated outcomes. Th e survey fulfi lled Stanford Institutional Review Board exemption guidelines. To address when clinicians would use corticosteroids, we asked partici pants to rate their agreement (fi ve-point Likert scale) for the following situations: blood pressure poorly responsive to fl uid resuscitation and vasopressor therapy; an inappropriate response to ACTH testing [2]; and a history of treatment with corticosteroids within the prior 6 months. Likert responses were evalu ated by Pearson

Early norepinephrine resuscitation of life-threatening hypotensive septic shock: it can do the job, but at what cost?

Hamzaoui and colleagues [1] recently reported the eff ects of early norepinephrine for septic shock with lifethreatening hypotension. Th eir observations fi rst answer ‘yes’ to the question ‘Can norepinephrine alone restore mean arterial pressure (MAP) in septic shock?’ Second, as an answer to ‘How does norepinephrine alone restore MAP?’, they confi rm that norepinephrine restores MAP despite minimal fl uid administration through ‘recruiting’ unstressed volume while allowing increased contractility despite increasing afterload. Th e most critical question that remains unanswered, however, is ‘Should nor epinephrine alone be used to restore MAP in septic shock?’ If the price of fl uid resuscitation may be edema and organ failure, what may be the price of norepinephrine resuscitation? Th e fear is that the very same eff ects that allow norepinephrine to recruit unstressed volume, through alpha adrenergic eff ects on venous and arterial vasculature, might recruit volume to the macrovas culature, all the while decreasing fl ow in previously critically collapsible microvascular beds. Answers to this crucial question are still unclear. In two previous confl icting studies showing benefi cial [2] or detrimental [3] eff ects on microvascular blood fl ow, the discrepancies may have been due to diff erences in prior fl uid therapy and ensuing preload reserve. In order to determine the optimal use of norepinephrine, future studies of microcirculation and perfusion should either optimize on an indicator of fl uid responsiveness during the fl uid therapy preceding norepinephrine treatment or rapidly wean the inevitable early norepinephrine infusion rate once the targeted MAP is obtained by screening for and addressing preload dependency during infusion rate decrements [4].

Is albumin use SAFE in patients with traumatic brain injury?

uid resuscitation in patients with traumatic brain injury. N Engl J Med 2007, 357:874-884 [1]. Background The Saline versus Albumin Fluid Evaluation study suggested that patients with traumatic brain injury resuscitated with albumin had a higher mortality rate than those resuscitated with saline. The SAFE investigators conducted a post hoc follow-up study of patients with traumatic brain injury who were enrolled in the study. Methods Objective: The aims of the study were to document baseline characteristics that are known to infl uence outcomes from traumatic brain injury in the albumin and saline groups and to compare death and functional neurologic outcomes in the two groups 24 months after randomization. Design: A post hoc follow-up study of patients with traumatic brain injury who were enrolled in the SAFE study. Setting: Intensive care units of 16 academic tertiary hospitals in Australia and New Zealand. Subjects: 460 patients 18 years or older with traumatic brain injury (i.e., a history of trauma, evidence of head trauma on a computed tomographic [CT] scan, and a score of ≤13 on the Glasgow Coma Scale [GCS]). Intervention: 231 (50.2%) received four percent albumin and 229 (49.8%) received saline. Outcomes: The primary outcome measures were the mortality rate and functional neurologic outcome 24 months after randomization. Multivariate logistic-regression was used to adjustment for baseline covariates known to be associated with increased mortality from traumatic brain injury (age older than 60 years, GCS score of 8, systolic pressure of <90 mm Hg, and traumatic subarachnoid hemorrhage). Analyses were conducted in all patients and in subgroups according to severity of traumatic brain injury. Results The subgroup of patients with GCS scores of 3 to 8 were classifi ed as having severe brain injury (160 [69.3%] in the albumin group and 158 [69.0%] in the saline group). Demographic characteristics and severity of brain injury were similar at baseline. At 2 years, 71 of 214 patients in the albumin group (33.2%) had died, as compared with 42 of 206 in the saline group (20.4%) (relative risk, 1.63; 95% confi dence interval [CI], 1.17 to 2.26; P=0.003). Among patients with severe brain injury, 61 of 146 patients in the albumin group (41.8%) died, as compared with 32 of 144 in the saline group (22.2%) (relative risk, 1.88; 95% CI, 1.31 to 2.70; P<0.001); among patients with GCS scores of 9 to 12, death occurred in 8 of 50 patients in the albumin group (16.0%) and 8 of 37 in the saline group (21.6%) (relative risk, 0.74; 95% CI, 0.31 to 1.79; P=0.50). Conclusions In this post hoc study of critically ill patients with traumatic brain injury, flresuscitation with albumin was associated with higher mortality rates than was resuscitation with saline. (Current Controlled Trials number, ISRCTN76588266.)

Disappearance of immunoglobulins in acute phase of influenza A infection

In February, 2005, a 52-year-old previously healthy man was admitted to our hospital intensive care unit with progressive dyspnoea and diminished consciousness. He had been experiencing fatigue, headache, abdominal pain, and nausea for 4 days. During transport to the hospital the patient had a cardiac arrest and needed to be resuscitated. On admission, his temperature was 35·2°C, blood pressure was 80/40 mm Hg, and heart rate was 130 beats per min. The patient was comatose and had respiratory failure; septic shock, acute myocardial infarction, and haemorrhagic shock were considered as possible causes. Treatment with antibiotics (cefotaxime and levofl oxacin) was initiated after taking samples of blood, sputum, stool, and urine for culture. Simultaneously, supportive treatment, including fl uid resuscitation, mechanical ventilation, and vasopressor support, was instituted. Chest radiography showed some signs of interstitial oedema. ECG was normal. These fi ndings, combined with normal cardiac biomarker levels, made myocardial infarction an unlikely diagnosis. Laboratory test results showed a left-shifted leucocytosis (19·6×10/L), haemo concentration (haemoglobin 195 g/L; haematocrit 0·56), and evidence of tissue hypoxaemia (lactic acid 16 mmol/L; arterial pH 6·82). Despite vasopressors and fl uid resuscitation, the patient remained hypotensive. Low colloid osmotic pres sure as a result of capillary leak seemed to be partly responsible. Low albumin (16 g/L) and total protein (19 g/L) were indicative for this condition; hypogamma globulinaemia was present (IgA 0·23 g/L; IgM 0·12 g/L; IgG 1·0 g/L). Both high usage and impairment of liver synthesis function (the latter supported by hypo gammaglobulinaemia and an antithrombin of 0·20 U/mL) were possible explanations. Causes of hypogamma globulinaemia were considered. In this patient, without previous illnesses, medication, or recurring infections, a primary cause was unlikely. A viral infection as causal factor was considered. Serology for Epstein-Barr virus, cytomegalovirus, HIV, and parvovirus B19 was negative. Infl uenza A (H3N2) was isolated in sputum samples (2nd and 4th day in hospital). All other cultures remained negative. Although a diagnosis was established, the patient’s clinical condition had vastly improved, and, therefore, antiviral therapy was not initiated. Liver synthesis function recovered after a few days. After 9 days the patient was transferred to the ward and was discharged after another 5 days. Until fi nal followup in February, 2006, there had been no recurrence of illness and immunoglobulin concentrations remained normal (fi gure). Because of a remaining monoclonal IgG-λ in an otherwise normal protein γ-fraction, a fi rst episode of the rare systemic capillary leak syndrome has to be considered as well, although this is less likely. Reports of shock caused by viral infections are limited, and, in most cases, associated with underlying disease or occur in immune compromised patients. Although hypogamma globulinaemia indicated a state of immunodefi ciency, we have no reason to believe this was the case before admission because our patient did not have a history of recurrent infections and we could not identify a preexisting immune defi ciency in a plasma sample taken several weeks before admission (fi gure). Immunoglobulin concentrations returning to normal on recovery gave further evidence to support the hypothesis that the transient hypogammaglobulinaemia was caused by infl uenza A infection. In mice, depletion of B cells by infl uenza virus has been demonstrated. Alternatively, since anti-infl uenza antibodies can promote the resolution of primary infl uenza infection in animals, the severity of the clinical course in this case could have been caused by the lack of an antibody response. Common fl u-like diseases can have serious complications even in healthy persons who are not considered part of a high-risk population. Hypogammaglobulinaemia in a non-immunocompromised patient with sepsis syndrome should prompt the clinician to consider a viral cause and should allow for rapid institution of antiviral therapy.

Sepsis: from basics to clinical practice - Editorial

Severe sepsis and septic shock are common clinical problems from the newborn to elderly people. The patients often need to be treated in intensive care units. The mortality in septic shock is high. It has been estimated that about 150,000 and 200,000 yearly deaths are due to sepsis in the European Union and the United States, respectively. New developments in the treatment possibilities of sepsis have, however, been achieved during the last few years, and it may be easier to tackle this major clinical problem more effectively than before. This issue of the Journal includes a special section on sepsis. In the seven articles, both molecular and clinical aspects are discussed in the light of recent discoveries and modern clinical practice. Animal models for sepsis have revealed promising immunomodulating agents for the treatment of sepsis. Most models for sepsis lack an infectious focus. Many studies have addressed a variety of immunomodulating strategies, but the results have often been discouraging. The differences in the sepsis models as well as their advantages and disadvantages are discussed by Schultz and van der Poll (p. 573±81). They conclude that the use of a combination of models to test new therapeutic agents would be the most likely successful route for preclinical studies. Of the new molecules studied, activated protein C has been shown to be particularly effective in preventing microvascular thrombosis. Dr. Esmon provides a comprehensive review of the biology of the protein C pathway and of the features making it unique in controlling both microvascular coagulation and acute in ammatory response (p. 598±605). The review describes the complex molecular pathways, in which protein C is involved in these two contexts. Recent data suggest that activated protein C reduces the death rate from sepsis. Some concerns have also been raised, and the clinical studies published need further support. Accordingly, several such studies are underway. Another potential concern is the high cost, which may restrict the world-wide use of activated protein C. We may expect that the next few years will clarify the role of activated protein C in clinical practice. Both the in ammatory reaction and concurrent activation of the anti-in ammatory mechanisms in the host are central to the pathophysiology of sepsis. The balance between the two opposing groups of reactions may be critical for the outcome of the sepsis patient. Activated phagocytes and high circulating levels of pro-in ammatory cytokines occur in patients at risk for multi-organ failure. Impaired natural (innate) and adaptive immune reactions also predispose the patients to the development of secondary infections. As well as therapies aiming at modifying the natural course of in ammatory responses, the in ammatory markers may also offer tools for the diagnosis of sepsis and the degree of organ failure associated with it. Takala et al. (p. 614± 23) summarize their own results and provide evidence that markers like CD11b on phagocytes and serum interleukin-8 can discriminate patients at high risk for organ dysfunction. Such discrimination would be useful in targeting treatment for severe infections and in focusing anti-in ammatory therapies on the right type of patients. Severe sepsis is today a common disease accounting for up to 10% of hospital admissions. Dr. Vincent and co-workers give a practical view on sepsis and septic shock covering the supportive measures such as uid resuscitation and vasopressors (p. 606±13). They also review the use of activated protein C in the world-wide PROWESS trial. Three other articles focus on more speci®c issues in the treatment of sepsis, namely the treatment of impaired perfusion of the affected organs (Ruokonen et al. (p. 590±7)), the use of corticosteroids (Chadda and Annane (p. 582± 9)) and the management of meningoccocal disease (Wall (p. 624±34)). The main causes of septic death are multiple organ failure and concurrent hypotension. The treatment of haemodynamics consists of appropriate uid therapy and vasoactive drugs aiming to correct hypotension and inappropriately low cardiac output (Ruokonen et al. (p. 590±7)). While norepinephrine is the drug of choice for low vascular resistance, insuf®cient myocardial function is commonly treated with dobutamine. The use of norepi-

Early and Proper Diagnosis of Sepsis—Still a Problem and Matter of Controversy

The disappointing results of new adjunctive therapies for sepsis in large clinical studies prompted the late Roger Bone to suggest that “we should spend more time to achieve an accurate diagnosis and less time for searching a magic bullet” [1]. However, not only important for valid clinical investigation, accurate and early diagnosis of sepsis may also help improve patient outcome. Because of the importance of the subject matter, we asked experts in the ~eld to discuss some new aspects and recent ~ndings that might be helpful in improving the diagnosis of sepsis. Sepsis is nowadays de~ned as a systemic response to severe infections [2]. Sepsis is diagnosed when clinical evidence of infection is accompanied by signs of systemic in_ammation. These statements have been translated to a set of clinical and laboratory criteria for the diagnosis of sepsis. For clinical purposes, the diagnostic criteria of sepsis should identify patients at an early stage of the syndrome, prompting clinicians to search for and treat infection, apply appropriate supportive therapy, and monitor for organ failure and other complications. For study purposes, the diagnostic criteria of sepsis should identify patients who would potentially bene~t from new (immunomodulatory) therapeutic approaches. Multicenter immunomodulatory trials of sepsis conducted 10 years ago started using uniform clinical diagnostic criteria for identifying septic patients [3]. These studies helped de~ne what sepsis means when certain clinical and laboratory criteria are used. Based on the characteristics of the patients included in these trials, Roger Bone published important clinical data regarding the epidemiology of sepsis (as de~ned by those criteria) and proposed using a set of criteria for “early detection and treatment of a group of very high-risk patients with sepsis” [4]. The term “sepsis syndrome” was coined for this group of patients. The “sepsis syndrome” was diagnosed when clinical evidence of infection was accompanied by evidence of in_ammation and poor organ perfusion or of organ dysfunction. Clinical evidence of infection meant that there was no longer a need to have bacteriological evidence such as positive blood cultures and that clinical criteria suf~ced [4,5]. To further clarify inadequacies arising from the de~nition of the sepsis syndrome, members of the American College of Chest Physicians and the American Society of Critical Care Medicine (ACCP/SCCM) provided a new set of de~nitions for both clinical and experimental applications [2]. The “systemic in_ammatory response syndrome” (SIRS) was de~ned as the presence of two or more of the following diagnostic criteria: changes in body temperature (fever or hypothermia), changes in white blood cell counts (leukocytosis or leukopenia or increases in immature neutrophils), tachycardia, and tachypnea. Sepsis was then de~ned as the systemic in_ammatory response to an infection, severe sepsis as sepsis associated with organ dysfunction, hypoperfusion, or hypotension, and septic shock as persistence of hypoperfusion or hypotension despite _uid resuscitation. The diagnostic criteria thus comprises signs of in_ammation and evidence of infection to diagnose sepsis and signs of remote organ failure to address the severity of the in_ammatory response. Some points are of importance: First, common signs of in_ammation such as changes in body temperature, changes in leukocyte count, changes in neutrophil granulation, tachycardia etc. may have an infectious or non-infectious etiology and are neither speci~c nor sensitive for sepsis. Of note, only two signs, namely changes in leukocyte counts and changes in body temperature can be directly related to in_ammation whereas tachycardia and tachypnea cannot. Second, the disappointing results of immunomodulatory trials in septic patients have raised doubts as to whether clinical and laboratory criteria alone may suf~ce in identifying groups of patients who would most likely bene~t from such therapies. We note that the diagnosis of sepsis, an important ~rst step for both clinicians and clinical investigator, still has many pitfalls. These shortcomings of the de~nitions and diagnostic criteria call for new diagnostic tools and parameters. Some parameters may be needed in early clinical identi~cation of such patients, others may be important in gauging the in_ammatory response and monitoring the immune status of the patient, still others may help identify subgroups of septic patients who may bene~t from proor anti-in_ammatory therapies. In this issue of the journal, parameters and markers of the septic response and their scienti~c and clinical