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Critical care papers


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Reducing the risk of major elective surgery: randomised controlled trial of preoperative optimisation of oxygen delivery. Wilson J, Woods I, Fawcett J et al. Br Med J 1999; 318: 1099-1103. 

In the United Kingdom, most patients are taken directly from the general ward to the operating theatre before major elective surgery. The extent of peri-operative monitoring is variable and the site of post-operative care will depend on the premorbid state and the availability of ITU or HDU beds. Optimisation of oxygen delivery has been shown to improve the outcome of high-risk patients undergoing major surgery. This can be achieved by the use of intravenous fluids and inotropic agents. The aim of this study was to determine whether preoperative optimisation of oxygen delivery improved post-operative outcome and to determine whether the inotropic agents, adrenaline and dopexamine, had similar effects. The study was performed as randomised controlled trial in a district general hospital. In total 138 patients undergoing major elective surgery (aneurysm surgery, upper GI or anterior resections, cystectomy) and at risk of developing post-operative complications because of coexisting disease states were randomised into three groups. Two groups received invasive haemodynamic monitoring, fluid and either adrenaline or dopexamine to increase oxygen delivery. The third (control) group received routine peri-operative care. The main outcome measures were hospital morbidity and mortality. Overall, 3/92 (3%) preoptimised patients died compared with 8/46 (17%; p=0.007) in the control group. There was no difference in mortality between the treatment groups, but 14/46 (30%) in the dopexamine group developed complications compared with 24/46 (52%) in the adrenaline group and 28/46 (61%) in the control group. The use of dopexamine was associated with a decreased hospital stay. It was concluded that routine pre-operative optimisation of patients undergoing major surgery resulted in a significant improvement in peri-operative care.

E5 murine monoclonal antiendotoxin antibody in gram-negative sepsis. Angus D C, Birmingham M C,  Balk R A et alJAMA 2000;  283:  1723-1730.

Despite improvements in intensive care medicine and an increased understanding of the pathophysiology of gram-negative sepsis, over the last 20 years the overall mortality of this condition has failed to improve.  Endotoxin is believed to play a central role in the pathophysiology of gram-negative sepsis.  Encouraging results from animal studies has lead to large-scale clinical trials of immunomodulatory therapies in septic patients.  One such approach has been the use of monoclonal antibodies directed against endotoxin.  The results of clinical studies published to date have been disappointing.  The aim of this study was to assess the efficacy and safety of E5, a murine monoclonal anti-endotoxin IgM antibody, in patients with gram-negative sepsis. A multicentre double-blind, randomised placebo-controlled trial was conducted in 136 US intensive care units.  Patients with clinical features of severe sepsis and documented or probable gram-negative infection were randomised to either two doses of E5 monoclonal antibody (n=550) or placebo (n=552).  The primary end-point was mortality at 14 days.  Secondary end-points were 28-day mortality, adverse events and mortality in subgroups presenting without clinical evidence of shock.  The trial was stopped after the second interim analysis as there was no significant difference in mortality between the two treatment groups (30% vs. 31%. p=0.67).  There was a similar profile of adverse events between the two groups.  It was concluded that despite adequate sample size and a high enrolment rate of patients with confirmed gram-negative sepsis, E5 did not improve the short-term survival.  Current study rationale and design should be carefully reviewed before further large-scale studies of patients with sepsis are conducted.

Effects of maximizing oxygen delivery on morbidity and mortality in high-risk surgical patients.  Lobo S M,  Salgado P F,  Castillo V G T et al.  Crit Care Med 2000;  28:  3396-3404. 

Surgical patients on the intensive care unit frequently have a postoperative period complicated by sepsis, systemic inflammatory response syndrome and organ dysfunction.  Such patients have often had episodes of haemodynamic instability during the perioperative period.  A correlation between oxygen debt in the intraoperative and early postoperative period and the evolution of organ failure and death has been previously demonstrated.  Survival of high risk patients may be related to supranormal increases in cardiac index and oxygen delivery.  The aim of the present study was to assess the effect of maximizing oxygen delivery on morbidity and mortality in patients over the age of 60 years with chronic disease undergoing major elective surgery.  A prospective randomised study of 37 high-risk patients undergoing major surgery was performed.  The haemodynamic and oxygen transport variable and outcome in 18 patients (protocol group) treated to maintain normal oxygen delivery were compared with 19 patients (control group) treated to maintain 'supranormal' values.  Therapy in both groups consisted of volume expansion and, when necessary, the use of dobutamine for the first 24 hours after surgery.  The study was terminated early because of a significant difference in 60-day mortality between the two groups (9/18 (50%) vs. 3/19 (16%) p<0.05).  The prevalence of of clinical and infectious complications was higher in the control group.  It was concluded that older patients with pre-existing cardiorespiratory disease undergoing major surgery had a reduced mortality and lesser morbidity when dobutamine was utilised to maximize oxygen transport.

Complications of femoral and subclavian venous catheterization in critically ill patients.  Merrer J,  De Jonghe B,  Golliot F et al.  JAMA 2001;  286:  700-707.

Central venous catheterisation is often necessary to treat critically ill patients in intensive care units (ICU).  However, the procedure can lead to serious and occasionally life-threatening complications.  The choice of insertion site can influence the the incidence and type of such complications.  These can be mechanical (e.g. haematoma, pneumothorax, arterial puncture), infections (site or systemic infection) or thrombotic (partial or complete vessel occlusion).  The aim of this study was to compare the mechanical, infectious and thrombotic complications of femoral and subclavian catheterisation in the setting of a randomised controlled trial.  Between December 1997 and July 2000 in 8 ICUs, 289 adult patients receiving a first central venous catheter were randomised to under go either femoral (n=145) or subclavian (n=144) line insertion. The rate and severity of complications were compared.  Femoral catheterisation was associated with a higher overall incidence of infectious complications and of major infectious complications as well as of overall thrombotic complications and complete vessel thrombosis.  The rate of overall and major mechanical complications were similar between the two groups.  Risk factors for mechanical complications were duration of insertion and insertion during the night.  The only factor associated with infectious complications was femoral catheterisation.  Antibiotic administration via the catheter decreased the risk of infectious complications.  Femoral catheterisation was the only risk factor for thrombotic complications.  It was concluded that femoral venous catheterisation is associated with a greater risk of infectious and thrombotic complications than subclavian catheterisation in ICU patients.

Early goal-directed therapy in the treatment of severe sepsis and septic shock.  Rivers E,  Nguyen B,  Havstad S et al.  N Eng J Med 2001;  345:  1368-1377.

Severe sepsis and septic shock are characterised by circulatory abnormalities including intravascular volume depletion, peripheral vasodilatation, myocardial depression and increased metabolism leading to an imbalance between systemic oxygen delivery and oxygen demand. This results in global tissue hypoxia and shock. These physiological derangements frequently occur in septic patients on wards and in emergency departments. Goal-directed therapy is commonly used in the management of severe sepsis and septic shock within the intensive care unit (ICU). This approach involves adjustments of cardiac preload, afterload and contractility to achieve a balance between oxygen delivery and demand. The aim of this study was to evaluate the efficacy of early goal-directed therapy before admission to the ICU. Patients admitted to an emergency department with severe sepsis or septic shock were randomly assigned to either six hours of goal-directed therapy or standard therapy prior to admission to the ICU. Clinicians who subsequently assumed the care of the patient were blinded to the treatment assignment within the emergency department. The primary end-point was in-hospital mortality. Secondary end-points with respect to resuscitation and APACHE II scores were also measured for 72 hours. Of the 263 patients enrolled, 130 were randomised to early goal-directed therapy and 133 to standard therapy. There was no difference between the groups with regard to baseline characteristics. In-hospital mortality was 31% in the early goal-directed therapy group and 47% in the standard therapy group (p=0.009). During the study period patients receiving goal-directed therapy had a higher mean central venous oxygen saturation and a lower arterial lactate and base deficit. Mean APACHE II scores were significantly lower in early goal-directed therapy group (p<0.001). It was concluded that early goal-directed therapy provides significant benefits with respect to outcome in patients with severe sepsis and septic shock.

Effects of selective decontamination of digestive tract on mortality and acquisition of resistant bacteria in intensive care:  a randomised controlled trial.  de Jonge E,  Schultz M J,  Spanjaard L et al.  Lancet 2003;  362:  1011-1016. 

Nosocomial infections contribute substantially to morbidity and mortality of patients treated in intensive care units.  Most of these infections are thought to be preceded by oropharyngeal and intestinal colonisation with pathogenic microorganisms.  Selective decontamination of the digestive tract (SDD) is an infection-prevention regime aimed at reducing the incidence and consequences of nosocomial infection.  The aim of this study was to assess the effect of SDD on intensive care unit (ICU) and hospital mortality and on the acquisition of resistant bacteria in adult patients admitted to intensive care.  The study was a prospective randomised uncontrolled clinical trial of 934 patients admitted to a medical and surgical intensive care unit.  Patients were randomly assigned to either enteral polymyxin E, tobramycin and amphotericin B combined with an initial 4-day course of intravenous cefotaxime (n = 466) or standard treatment (n = 468).  The primary endpoints were ICU and hospital mortality and the acquisition of resistant bacteria.  In the SDD group 69 (15%) patients died in the ICU compared with 107 (23%) in the control group (p = 0.002).  Hospital mortality was lower in the SDD group than in the control group (113 vs. 146.  p = 0.02).  During their stay in intensive care, colonisation with gram-negative bacteria resistant to ceftazidime, ciprofloxacin, imipenem, polymyxin E or tobramycin occurred in 61 (16%) of the 378 SDD patients and in 104 (26%) of the 395 patients in the control group (p = 0.001).  No patient in either group was colonised with methicillin-resistant Staphylococcus aureus.  It was concluded that in a setting with low prevalence of vancomycin-resistant enterococcus and MRSA, SDD can decrease ICU and hospital mortality and colonisation with resistant gram-negative aerobic bacteria.

Perioperative beta-blocker therapy and mortality after major noncardiac surgery.  Lindenauer P K,  Pekow P,  Wang K et al.  N Engl J Med 2005;  353:  349-361.

More than 20 million operations are performed annually at hospitals throughout the United States and although advances in operative and anaesthetic techniques have reduced the risks, some 1 in 10 patients can be expected to have a complication within 30 days of major surgery.  Postoperative cardiovascular complications are associated with significant risk of other complications and death.  Despite limited evidence from randomised trials, perioperative treatment with beta-blockers is now widely advocated.  The aim of this study was to assess the use of perioperative beta-blockers and their association with in-hospital mortality in routine clinical practice.  A retrospective cohort study was undertake of patients 18 years of age or older who underwent major non-cardiac surgery in 2000 and 2001 at 329 hospitals through out the United States.  Propensity-score matching was used to adjust for differences between patients who received perioperative beta-blockers and those who did not receive such therapy.  In-hospital mortality was compared using multivariable logistic modelling.  Of 782,969 patients 85% had no recorded contraindication to beta-blockers of whom 18% received such treatment during the first two hospital days, including 14% patients with a Revised Cardiac Risk Index (RCRI) of 0 and 44% with a score of 4 or higher.  The relationship between perioperative beta-blocker treatment and risk of death varied directly with cardiac risk.  In patients with RCRI score of 2,3,4 or more, the adjusted odds ratio for death in hospital were 0.88 (95% CI, 0.71 (95% CI 0.63-0.80) and 0.58 (95% CI 0.50-0.67) respectively.  It was concluded that perioperative beta-blocker therapy is associated with a reduced risk of in-hospital death amongst high-risk but not low-risk patients undergoing major noncardiac surgery.  Patient safety maybe enhanced by increasing the use of beta-blockers in high-risk patients.

Randomised clinical trial assessing the effect of Doppler-optimized fluid management on the outcome after elective colorectal resection.  Noblett S E,  Snowden C P,  Shenton B K et al.  Br J Surg 2006;  93:  1069-1076. 

Recent developments in multimodal care and enhanced surgical recovery programmes after elective colorectal surgery have identified potential improvements in outcome after major bowel resection. The role of perioperative fluid management remains under debate.  Various fluid management regimes have been proposed with the aim to avoid tissue hypoperfusion and activation of the systemic inflammatory response.  Oesophageal doppler monitoring is a minimally invasive method of accurately determining haemodynamic status in the perioperative period.  Accurate guidance of intraoperative fluid administration using oesophageal doppler monitoring may reduce the risk of perioperative hypovolaemia.  The aim of this study was to assess whether protocolized fluid administration using oesophageal doppler may improve the postoperative outcome in patients undergoing elective colorectal surgery.  A total of 108 patients were recruited into a double-blind prospective randomised controlled trial.  An oesophageal doppler probe was placed in all patients.  The control group received perioperative fluid at the discretion of the anaesthetist, whereas the intervention group received additional colloid boluses based on doppler assessment.  Primary outcome was length of postoperative hospital stay.  Secondary outcomes were morbidity, return of gastrointestinal function and cytokine markers of the systemic inflammatory response.  Standard preoperative and postoperative management was used in all patients.  Demographic and surgical details were similar in the two groups.  Aortic flow time, stroke volume, cardiac output and cardiac index during the intraoperative period was higher in the intervention group (p<0.05).  The intervention group had a reduced postoperative stay (7 vs. 9 days. p=0.005), fewer intermediate or major postoperative complications (2 vs. 15. p=0.043) and tolerated diet earlier (2 vs. 4 days. p=0.029).  There was a reduced rise in perioperative level of the cytokine interleukin 6 in the intervention group (p=0.039).  It was concluded that a protocol based fluid optimization programme using intraoperative oesophageal doppler monitoring leads to a shorter hospital stay and decreased morbidity in patients undergoing elective colorectal surgery.

Comparison of dopamine and norepinephrine in the treatment of shock.  De Backer D,  Biston P,  Devriendt J et al.  N Eng J Med 2010;  362:  779-789.

Both dopamine and norepinephrine are recommended as first-line vasopressor agents in the treatment of shock. There is a continuing controversy about whether one agent is superior to the other. In this multicentre, randomized trial, patients with shock were asigned to receive either dopamine or norepinephrine as first-line vasopressor therapy to restore and maintain blood pressure. When blood pressure could not be maintained with a dose of 20 µg per kilogram of body weight per minute for dopamine or a dose of 0.19 µg per kilogram per minute for norepinephrine, open-label norepinephrine, epinephrine, or vasopressin could be added. The primary outcome was the rate of death at 28 days after randomization.  Secondary end points included the number of days without need for organ support and the occurrence of adverse events. The trial included 1679 patients, of whom 858 were assigned to dopamine and 821 to norepinephrine. The baseline characteristics of the groups were similar. There was no significant between-group difference in the rate of death at 28 days (52.5% in the dopamine group and 48.5% in the norepinephrine group; odds ratio with dopamine, 1.17; 95% confidence interval, 0.97 to 1.42; P=0.10). However, there were more arrhythmic events among the patients treated with dopamine than among those treated with norepinephrine (207 events [24.1%] vs. 102 events [12.4%], P<0.001). A subgroup analysis showed that dopamine, as compared with norepinephrine, was associated with an increased rate of death at 28 days among the 280 patients with cardiogenic shock but not among the 1044 patients with septic shock or the 263 with hypovolemic shock (P=0.03 for cardiogenic shock, P=0.19 for septic shock, and P=0.84 for hypovolemic shock, in Kaplan–Meier analyses). It was concluded that although there was no significant difference in the rate of death between patients with shock who were treated with dopamine as the first-line vasopressor agent and those who were treated with norepinephrine, the use of dopamine was associated with a greater number of adverse events.


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