John D. Santamaria

A controlled trial of low-molecular-weight heparin (dalteparin) versus unfractionated heparin as anticoagulant during continuous venovenous hemodialysis with filtration

OBJECTIVE To compare the efficacy, safety, and cost of fixed-dose low-molecular-weight heparin (dalteparin) with adjusted-dose unfractionated heparin as anticoagulant for continuous hemofiltration. DESIGN Prospective, randomized, controlled clinical trial. SETTING University-affiliated adult intensive care unit PATIENTS All patients requiring continuous hemofiltration for acute renal failure or systemic inflammatory response syndrome (SIRS) were eligible. Fifty-seven patients were enrolled. Eleven were excluded, seven because of major protocol violations and four died before hemofiltration. INTERVENTIONS Patients received continuous venovenous hemodialysis with filtration with prefilter replacement at 500 mL/hr and countercurrent dialysate at 1000 mL/hr. Filters were primed with normal saline containing anticoagulant. Dalteparin-treated patients received a commencement bolus of 20 units/kg and a maintenance infusion at 10 units/kg/hr. Heparin-treated patients received a commencement bolus of 2000-5000 units and a maintenance infusion at 10 units/kg/hr, titrated to achieve an activated partial thromboplastin time in the patient of 70-80 secs. MEASUREMENTS AND MAIN RESULTS The primary outcome measure--time to failure of the hemofilter--was compared using survival analysis. Twenty-two patients (13 with acute renal failure and nine with SIRS; total, 41 filters) were randomized to heparin. Twenty-five patients (16 with acute renal failure and nine with SIRS; total, 41 filters) were randomized to dalteparin. Mean (SE) activated partial thromboplastin time in the heparin group was 79 (4.3) secs. Mean (SE) anti-factor-Xa activity in the six patients given dalteparin who were assayed was 0.49 (0.07). Mean (SE) prehemofiltration platelet count was 225 (35.5) x 10(9) for heparin and 178 (18.1) x 10(9) for dalteparin (p = .24, unpaired Students t-test). Mean (SE) prehemofiltration hemoglobin was 11.4 (0.61) g/dL for heparin and 10.6 (0.38) g/dL for dalteparin (p = .31, unpaired Students t-test). PRIMARY OUTCOME There was no significant difference in the time to failure between the two groups (p = .75, log rank test). For dalteparin, Kaplan-Meier (K-M) mean (SE) time to failure of the hemofilter was 46.8 (5.03) hrs. For heparin, K-M mean (SE) time to failure was 51.7 (7.51) hrs. The 95% CI for difference in mean time to failure was -13 to 23 hrs. The power of this study to detect a 50% change in filter life was >90%. SECONDARY OUTCOMES Mean (SE) reduction in platelet count during hemofiltration was 63 (25.8) x 10(9) for heparin and 41.8 (26.6) x 10(9) for dalteparin (p = .57, unpaired Students t-test). Eight patients given dalteparin and four patients given heparin had screening for heparin-induced thrombocytopenia; three of the dalteparin patients and one of the heparin patients were positive (p = 1.0, Fishers exact test). There were three episodes of trivial bleeding and two episodes of significant bleeding for dalteparin, and there were three episodes of trivial bleeding and four episodes of significant bleeding for heparin (p = .53, chi-square test). The mean (SE) decrease in hemoglobin concentration during hemofiltration was 0.51 (0.54) g/dL for heparin and 0.28 (0.49) g/dL for dalteparin (p = .75, unpaired Students t-test). The mean (SE) packed-cell transfusion volume during hemofiltration was 309 (128) mL for heparin and 290 (87) mL for dalteparin (p = .90, unpaired Students t-test). Daily costs, including coagulation assays, of hemofiltration were approximately 10% higher using dalteparin than with heparin. CONCLUSIONS Fixed-dose dalteparin provided identical filter life, comparable safety, but increased total daily cost compared with adjusted-dose heparin. Unfractionated heparin remains our anticoagulant of choice for continuous hemofiltration in intensive care.

Arterial carbon dioxide tension and outcome in patients admitted to the intensive care unit after cardiac arrest

BACKGROUND Arterial carbon dioxide tension (PaCO2) affects neuronal function and cerebral blood flow. However, its association with outcome in patients admitted to intensive care unit (ICU) after cardiac arrest (CA) has not been evaluated. METHODS AND RESULTS Observational cohort study using data from the Australian New Zealand (ANZ) Intensive Care Society Adult-Patient-Database (ANZICS-APD). Outcomes analyses were adjusted for illness severity, co-morbidities, hypothermia, treatment limitations, age, year of admission, glucose, source of admission, PaO2 and propensity score. We studied 16,542 consecutive patients admitted to 125 ANZ ICUs after CA between 2000 and 2011. Using the APD-PaCO2 (obtained within 24 h of ICU admission), 3010 (18.2%) were classified into the hypo- (PaCO2<35 mmHg), 6705 (40.5%) into the normo- (35-45 mmHg) and 6827 (41.3%) into the hypercapnia (>45 mmHg) group. The hypocapnia group, compared with the normocapnia group, had a trend toward higher in-hospital mortality (OR 1.12 [95% CI 1.00-1.24, p=0.04]), lower rate of discharge home (OR 0.81 [0.70-0.94, p<0.01]) and higher likelihood of fulfilling composite adverse outcome of death and no discharge home (OR 1.23 [1.10-1.37, p<0.001]). In contrast, the hypercapnia group had similar in-hospital mortality (OR 1.06 [0.97-1.15, p=0.19]) but higher rate of discharge home among survivors (OR 1.16 [1.03-1.32, p=0.01]) and similar likelihood of fulfilling the composite outcome (OR 0.97 [0.89-1.06, p=0.52]). Cox-proportional hazards modelling supported these findings. CONCLUSIONS Hypo- and hypercapnia are common after ICU admission post-CA. Compared with normocapnia, hypocapnia was independently associated with worse clinical outcomes and hypercapnia a greater likelihood of discharge home among survivors.

Changing cardiac arrest and hospital mortality rates through a medical emergency team takes time and constant review.

Objective: To determine the long-term impact of a medical emergency team on survival and to assess the utility of administrative data to monitor outcomes. Design: Prospective study of cardiac arrests and survival. Retrospective study of administrative data. Setting: University affiliated tertiary referral hospital in Melbourne, Australia. Patients: All patients admitted to hospital in three 6-month periods between 2002–2007 (prospective) and 1993–2007 (retrospective). Intervention: Implementation of a medical emergency team in November 2002. Measurements and Main Results: In the prospective analysis, rates of unexpected cardiac arrest and hospital mortality (referenced to 1000 patient-care days) were measured before (July–August 2002) and after (December 2002–May 2003, December 2004–May 2005, December 2006–May 2007) the introduction of the medical emergency team. Cardiac arrest rates decreased progressively from 0.78 per 1000 (95% confidence interval, 0.50–1.16) to 0.25 per 1000 (95% confidence interval, 0.15–0.39, p < .001), and hospital mortality from 0.58 per 1000 (95% confidence interval, 0.35–0.92) to 0.30 per 1000 (95% confidence interval, 0.20–0.46, p < .05); cardiac arrest rates achieved statistical significance at 2 yrs and hospital mortality at 4 yrs. Using administrative data adjusted for age, sex, case-mix, and comorbidity, hazard ratios for mortality for the three post implementation periods were statistically lower than for the 10 yrs pre implementation (0.85, 0.74, 0.65). The intensity of calling (calls/1000 patient-days) inversely correlated with cardiac arrest rate, unexpected mortality rate, and total hospital mortality rate. Conclusions: The introduction of a medical emergency team was associated with a progressive decline of unexpected cardiac arrests within 2 yrs, and of unexpected mortality within 4 yrs. This suggests that changes to organizational practice take time and benefits may not be immediately obvious. Such changes are reflected in total hospital mortality measured from administrative data and make monitoring simpler in the longer term. Finally, efforts to increase calling of emergency teams should reduce cardiac arrests and mortality.

An intensivist-led tracheostomy review team is associated with shorter decannulation time and length of stay: a prospective cohort study

IntroductionWithout specific strategies to address tracheostomy care on the wards, patients discharged from the intensive care unit (ICU) with a tracheostomy may receive suboptimal care. We formed an intensivist-led multidisciplinary team to oversee ward management of such patients. To evaluate the service, we compared outcomes for the first 3 years of the service with those in the year preceding the service.MethodsData were prospectively collected over the course of 3 years on ICU patients not under the care of the ear, nose, and throat unit who were discharged to the ward with a tracheostomy and compared with outcomes in the year preceding the introduction of the service. Principal outcomes were decannulation time, length of stay after ICU discharge, and stay of less than 43 days (upper trim point for the disease-related group [DRG] for tracheostomy). Analysis included trend by year and multivariable analysis using a Cox proportional hazards model. P values of less than 0.05 were assumed to indicate statistical significance. As this was a quality assurance project, ethics approval was not required.ResultsTwo hundred eighty patients were discharged with a tracheostomy over the course of a 4-year period: 41 in 2003, 60 in 2004, 95 in 2005, and 84 in 2006. Mean age was 61.8 (13.1) years, 176 (62.9%) were male, and mean APACHE (Acute Physiology and Chronic Health Evaluation) II score was 20.4 (6.4). Length of stay after ICU decreased over time (30 [13 to 52] versus 19 [10 to 34] days; P < 0.05 for trend), and a higher proportion of decannulated patients were discharged under the upper DRG trim point of 43 days (48% versus 66%; P < 0.05). Time to decannulation after ICU discharge decreased (14 [7 to 31] versus 7 [3 to 17] days; P < 0.01 for trend). Multivariate analysis showed that the hazard for decannulation increased by 24% (3% to 49%) per year.ConclusionAn intensivist-led tracheostomy team is associated with shorter decannulation time and length of stay which may result in financial savings for institutions.

Age of red blood cells and mortality in the critically ill

IntroductionIn critically ill patients, it is uncertain whether exposure to older red blood cells (RBCs) may contribute to mortality. We therefore aimed to evaluate the association between the age of RBCs and outcome in a large unselected cohort of critically ill patients in Australia and New Zealand. We hypothesized that exposure to even a single unit of older RBCs may be associated with an increased risk of death.MethodsWe conducted a prospective, multicenter observational study in 47 ICUs during a 5-week period between August 2008 and September 2008. We included 757 critically ill adult patients receiving at least one unit of RBCs. To test our hypothesis we compared hospital mortality according to quartiles of exposure to maximum age of RBCs without and with adjustment for possible confounding factors.ResultsCompared with other quartiles (mean maximum red cell age 22.7 days; mortality 121/568 (21.3%)), patients treated with exposure to the lowest quartile of oldest RBCs (mean maximum red cell age 7.7 days; hospital mortality 25/189 (13.2%)) had an unadjusted absolute risk reduction in hospital mortality of 8.1% (95% confidence interval = 2.2 to 14.0%). After adjustment for Acute Physiology and Chronic Health Evaluation III score, other blood component transfusions, number of RBC transfusions, pretransfusion hemoglobin concentration, and cardiac surgery, the odds ratio for hospital mortality for patients exposed to the older three quartiles compared with the lowest quartile was 2.01 (95% confidence interval = 1.07 to 3.77).ConclusionsIn critically ill patients, in Australia and New Zealand, exposure to older RBCs is independently associated with an increased risk of death.

The association of blood transfusion with mortality after cardiac surgery: cause or confounding? (CME)

BACKGROUND: Bleeding into the chest is a life‐threatening complication of cardiac surgery. Blood transfusion has been implicated as an important cause of harm associated with bleeding, based largely on studies demonstrating an independent association between transfusion and mortality. These studies did not, however, consider the possibility that bleeding may in itself be harmful, inasmuch as drains are inefficient at clearing blood from the chest and retained blood may compromise cardiac and lung function.

A phase 1 trial of nebulised heparin in acute lung injury

IntroductionAnimal studies of acute lung injury (ALI) suggest nebulised heparin may limit damage from fibrin deposition in the alveolar space and microcirculation. No human studies have been undertaken to date. We assessed the feasibility, safety and potential anticoagulant effects of administration of nebulised heparin to patients with ALI.MethodsAn open label phase 1 trial of four escalating doses of nebulised heparin was performed. A total of 16 ventilated patients with ALI were studied. The first group was administered a total of 50,000 U/day, the second group 100,000 U/day, the third group 200,000 U/day and the fourth group 400,000 U/day. Assessments of lung function included the PaO2/FiO2 ratio, lung compliance and the alveolar dead space fraction. Monitoring of anticoagulation included the activated partial thromboplastin time (APTT) and the thrombin clotting time. Bronchoalveolar lavage fluid was collected and the prothrombin fragment and tissue plasminogen activator levels were assessed. Analysis of variance was used to compare the effects of dose.ResultsNo serious adverse events occurred for any dose. The changes over time for the PaO2/FiO2 ratio, lung compliance and the alveolar dead space fraction levels were similar for all doses. A trend to increased APTT and thrombin clotting time levels was present with higher doses (P = 0.09 and P = 0.1, respectively). For the highest dose, the APTT reached 64 seconds; following cessation of nebulised heparin, the APTT fell to 39 seconds (P = 0.06). In bronchoalveolar lavage samples a trend to reduced prothrombin fragment levels was present with higher doses (P = 0.1), while tissue plasminogen activator levels were similar for all doses.ConclusionAdministration of nebulised heparin to mechanically ventilated patients with ALI is feasible. Nebulised heparin was not associated with any serious adverse events, and at higher doses it increased APTT levels. Larger trials are required to further investigate the safety and efficacy of nebulised heparin. In these trials due consideration must be given to systemic anticoagulant effects.Trial registrationAustralian Clinical trials registry ACTRN12606000388516.

Nebulized heparin is associated with fewer days of mechanical ventilation in critically ill patients: a randomized controlled trial

IntroductionProlonged mechanical ventilation has the potential to aggravate or initiate pulmonary inflammation and cause lung damage through fibrin deposition. Heparin may reduce pulmonary inflammation and fibrin deposition. We therefore assessed whether nebulized heparin improved lung function in patients expected to require prolonged mechanical ventilation.MethodsFifty patients expected to require mechanical ventilation for more than 48 hours were enrolled in a double-blind randomized placebo-controlled trial of nebulized heparin (25,000 U) or placebo (normal saline) 4 or 6 hourly, depending on patient height. The study drug was continued while the patient remained ventilated to a maximum of 14 days from randomization.ResultsNebulized heparin was not associated with a significant improvement in the primary end-point, the average daily partial pressure of oxygen to inspired fraction of oxygen ratio while mechanically ventilated, but was associated with improvement in the secondary end-point, ventilator-free days amongst survivors at day 28 (22.6 ± 4.0 versus 18.0 ± 7.1, treatment difference 4.6 days, 95% CI 0.9 to 8.3, P = 0.02). Heparin administration was not associated with any increase in adverse events.ConclusionsNebulized heparin was associated with fewer days of mechanical ventilation in critically ill patients expected to require prolonged mechanical ventilation. Further trials are required to confirm these findings.Trial registrationThe Australian Clinical Trials Registry (ACTR-12608000121369).

Prospective population‐based cohort of inflammatory bowel disease in the biologics era: Disease course and predictors of severity

We have previously found high incidence of inflammatory bowel disease (IBD) in Australia. A population‐based registry was established to assess disease severity, frequency of complications, and prognostic factors.

Mechanisms by which systemic salbutamol increases ventilation

Background and objective:  Salbutamol (SAL) has systemic effects that may adversely influence ventilation in asthmatic patients. The authors sought to determine the magnitude of this effect and mechanisms by which i.v. SAL affects ventilation.