Factors associated with increased risk of readmission to intensive care in Australia.

PURPOSE: To determine the epidemiology, in-hospital mortality, trends, patient characteristics and predictors of intensive care unit (ICU) readmission in Australia. METHODS: A retrospective longitudinal study of data for 38 Australian ICUs extracted from the Australian and New Zealand Intensive Care Society Adult Patient Database (ANZICS-ADP) for the years 2000-2007. Demographic, diagnostic, physiological and outcome data were analysed. A multivariate model was constructed to identify risk factors for ICU readmission. Outcomes examined included observed and risk-adjusted in-hospital mortality. RESULTS: A total of 247,103 patients were discharged alive from their first ICU admission; 13,598 (5.5%) were readmitted at least once. Variables associated with an odds ratio greater than 1.05 for readmission (p < 0.001) were an initial ICU admission source other than elective surgery, any chronic health variable on severity scoring, tertiary hospital ICU and discharge between 6 p.m. and 6 a.m. Five initial diagnoses were associated with an odds ratio (OR) greater than 2 for readmission (p < 0.001). In-hospital mortality in readmitted patients was 20.7% compared with 4.4% in those not readmitted. Readmission rates have not changed over the study period. After adjustment for illness severity and readmission propensity, ICU readmission remained significantly associated with in-hospital mortality (OR 5.4, 95%, confidence interval (CI) 5.1-5.7). CONCLUSIONS: Many risk factors for increased ICU readmission were identified in this study including ICU discharge between 6 p.m. and 6 a.m. This was the only modifiable variable studied. Prospective studies are required to identify other factors and to determine whether interventions may reduce ICU readmission and its high associated in-hospital mortality.

Outcome-based clinical indicators for intensive care medicine.

The clinical indicator is a tool used to monitor the quality of health care. Its use in the Intensive Care Unit (ICU) is desirable for many reasons: the maintenance of minimum standards, the development of best practice and the delivery of cost-effective health care. The utility of clinical indicators in ICU is limited by the lack of universal, robust, transparent, evidence-based and risk-adjusted measures of quality, and the difficulties in defining "quality care" and "good outcome". Monitoring of adverse events, system descriptors, and resource indicators is valuable but they have a limited relationship to the quality of care. ICU mortality prediction models provide a global measure of quality and, despite their inherent deficiencies, remain one of the most robust and useful clinical indicators.

How doctors discuss major interventions with high risk patients: an observational study.

OBJECTIVE: To investigate the difficulties doctors face in discussing treatment options with patients with acute, life threatening illness and major comorbidities. DESIGN: Observational study of doctor-patient interviews based on a standardised clinical scenario involving high risk surgery in a hypothetical patient (played by an actor) with serious comorbidities. PARTICIPANTS: 30 trainee doctors 3-5 years after graduation. MAIN OUTCOME MEASURES: Adequacy of coverage of various aspects was scored from 3 (good) to 0 (not discussed). RESULTS: The medical situation was considered to be well described (median score 2.7 (interquartile range 2.1-3.0)), whereas the patient's functional status, values, and fears were poorly or minimally addressed (scores 0.5 (0.0-1.0), 0.5 (0.0-1.0), and 0.0 (0.0-1.5), respectively; all P < 0.001 v score for describing the medical situation). Twenty nine of the doctors indicated that they wished to include the patient's family in the discussion, but none identified a preferred surrogate decision maker. Six doctors suggested that the patient alone should speak with his family to reach a decision without the doctor being present. The doctors were reluctant to give advice, despite it being directly requested: two doctors stated that a doctor could not give advice, while 17 simply restated the medical risks, without advocating any particular course. Of the 11 who did offer advice, eight advocated intervention. CONCLUSIONS: Doctors focused on technical medical issues and placed much less emphasis on patient issues such as functional status, values, wishes, and fears. This limits doctors' ability to offer suitable advice about treatment options. Doctors need to improve their communication skills in this difficult but common clinical situation.

Comparative analysis of flow cytometry and polymerase chain reaction for the detection of minimal residual disease in childhood acute lymphoblastic leukemia.

Minimal residual disease (MRD) is an independent prognostic factor in childhood acute lymphoblastic leukemia (ALL). The most widely applied MRD assays in ALL are flow cytometric identification of leukemia immunophenotypes and polymerase chain reaction (PCR) amplification of antigen-receptor genes. We measured MRD by both assays in 227 patients with childhood B-lineage ALL. Of 1375 samples (736 bone marrow and 639 peripheral blood) examined, MRD was <0.01% in 1200, and > or =0.01% in 129 by both assays; MRD levels measured by the two methods correlated well. Of the remaining 46 samples, 28 had MRD > or =0.01% by flow cytometry but <0.01% by PCR. However, PCR (which had a consistent sensitivity of 0.001%) detected leukemic gene rearrangements in 26 of these 28 samples. Conversely, in 18 samples, MRD was > or =0.01% by PCR but <0.01% by flow cytometry. In nine of these samples, flow cytometry had a sensitivity of 0.001%, and detected aberrant immunophenotypes in eight samples. Therefore, the two most widely used methods for MRD detection in ALL yield concordant results in the vast majority of cases, although the estimated levels of MRD may vary in some. The use of the two methods in tandem ensures MRD monitoring in all patients.

Safety and feasibility of an insulin adjustment protocol to maintain blood glucose concentrations within a narrow range in critically ill patients in an Australian level III adult intensive care unit.

OBJECTIVE: Recent data have shown a link between normal blood glucose levels and improved outcomes in intensive care patients. We wished to develop an insulin adjustment protocol for an adult intensive care unit to maintain blood glucose concentrations safely within a narrow range. METHODS: After a 6 month introductory period, an observational study was conducted during a 10 month period in an Australian level III intensive care unit to assess the safety and feasibility of an insulin adjustment protocol to maintain blood glucose concentrations safely within a narrow range. The protocol included a variable insulin infusion, a constant caloric source and frequent blood glucose level monitoring to detect and prevent hypoglycaemia. RESULTS: Over the 10 month period a total of 148 patients were studied using the protocol and represented 13 % of all intensive care unit admissions during this period. In total, there were 12,623 patient hours 'on protocol', with 5,603 blood glucose levels performed. The mean morning blood glucose level was 6.5 mmol/L and 49% of blood glucose levels were within the target range of 4.1 - 7.0 mmol/L. There were four recorded incidents of hypoglycaemia, defined as a blood glucose level of less than 2.2 mmol/L, the lowest at 1.5 mmol/L being the only symptomatic episode. The incidence of hyperglycaemia (blood glucose level > 10 mmol/L) was 13 % of all blood glucose level measurements. CONCLUSIONS: The insulin adjustment protocol with a constant caloric source and frequent blood glucose level monitoring was found to be safe and feasible in maintaining blood glucose concentrations within a narrow range in a mixed adult intensive care unit population.

Quantification of minimal residual disease in T-lineage acute lymphoblastic leukemia with the TAL-1 deletion using a standardized real-time PCR assay.

Hematologic relapse remains the greatest obstacle to the cure of children with acute lymphoblastic leukemia (ALL). Recent studies have shown that patients with increased risk of relapse can be identified by measuring residual leukemic cells, called minimal residual disease (MRD), during clinical remission. Current PCR methods, however, for measuring MRD are cumbersome and time-consuming. To improve and simplify MRD assessment, we developed a real-time quantitative PCR (RQ-PCR) assay for detection of leukemic cells that harbor the TAL-1 deletion. We studied serial dilutions of leukemic DNA and found the assay had a sensitivity of detection of one leukemic cell among 100,000 normal cells. We then investigated 23 samples from eight children with ALL in clinical remission. We quantified residual leukemic cells by using the TAL-1 RQ-PCR assay and by using limiting dilution analysis. In 17 samples, both methods detected MRD levels > or =0.001%. The percentages of leukemic cells measured by the two methods correlated well (r2 = 0.926). In the remaining six samples, both methods detected fewer than 0.001% leukemic cells. We conclude the TAL-1 RQ-PCR assay can be used for rapid, sensitive and accurate assessment of MRD in T-lineage ALL with the TAL-1 deletion.

Tandem application of flow cytometry and polymerase chain reaction for comprehensive detection of minimal residual disease in childhood acute lymphoblastic leukemia.

Children with acute lymphoblastic leukemia (ALL) with > or = 0.01% leukemic cells in the bone marrow after remission induction are at a greater risk of relapse. The most promising methods of detecting minimal residual disease (MRD) are flow cytometric identification of leukemia-associated immunophenotypes and polymerase chain reaction (PCR) amplification of antigen-receptor genes. However, neither assay can be applied to all patients. Moreover, both assays carry the risk of false-negative findings due to clonal evolution. The simultaneous use of both assays might resolve these problems, but the correlation between the methods is unknown. We studied serial dilutions of normal and leukemic cells by flow cytometry and PCR amplification of IgH genes and found the two methods highly sensitive (one leukemic cell among 10(4) or more normal cells), accurate (r2 was 0.999 for flow cytometry and 0.960 for PCR by regression analysis) and concordant (r2 = 0.962). We then examined 62 bone marrow samples collected from children with ALL in clinical remission. In 12 samples, both techniques detected MRD levels > or = 1 in 10(4). The percentages of leukemic cells measured by the two methods correlated well (r2 = 0.978). Of the remaining 50 samples, 48 had MRD levels < 1 in 10(4). In only two samples results were discordant: 2 in 10(4) and 5 in 10(4) leukemic cells by PCR but < 1 in 10(4) by flow cytometry. We conclude that immunologic and molecular techniques can be used in tandem for universal monitoring of MRD in childhood ALL.

Sepsis-induced vasoparalysis does not involve the cerebral vasculature: indirect evidence from autoregulation and carbon dioxide reactivity studies.

We have studied cerebral autoregulation and vasoreactivity to carbon dioxide in 10 patients with the sepsis syndrome receiving intensive therapy. All patients were sedated with infusions of midazolam and fentanyl, and their lungs were ventilated mechanically with oxygen-air to maintain normoxia and normocapnia. Inotropic support and antibiotics were administered as necessary. During a period of constant level of sedation and stable haemodynamics, cerebral autoregulation was tested by increasing mean arterial pressure (MAP) by 23 (SD 2) mm Hg from baseline with an infusion of phenylephrine and simultaneously recording middle cerebral artery blood flow velocity (vmca) using transcranial Doppler ultrasonography. Carbon dioxide reactivity was tested by varying PaCO2 between 3.0 and 7.0 kPa and simultaneously recording vmca. There was no significant change in vmca (57 (22) and 59 (23) cm s-1) during the increase in MAP (75 (11) to 98 (10) mm Hg). The mean index of autoregulation (IOR) was 0.92 (SEM 0.03), which was not significantly different from 1, indicating near perfect autoregulation. Although absolute carbon dioxide reactivity was lower than reported previously in awake subjects, relative carbon dioxide reactivity was within normal limits for all patients (11.6 (SEM 0.8) cm s-1 and 20.3 (3) % kPa-1, respectively). We conclude that cerebral carbon dioxide reactivity and pressure autoregulation remained intact in patients with the sepsis syndrome, providing indirect evidence that at least in the early stages of the syndrome, the widespread sepsis-induced vasoparalysis does not involve the cerebral vasculature.

Prolonged use of isoflurane in a patient with tetanus.

We describe a patient with tetanus, who received isoflurane for sedation to facilitate controlled mechanical ventilation. Isoflurane was administered for 34 days, resulting in a sustained serum inorganic fluoride ion concentration in excess of 50 mumol litre-1 and a peak serum inorganic fluoride ion concentration of 87 mumol litre-1. Although these concentrations are potentially nephrotoxic, no toxicity was evident clinically.

Propofol to provide sedation after coronary artery bypass surgery. A comparison of two fixed rate infusion regimens.

Propofol (2,6, di-isopropylphenol) was given by continuous intravenous infusion to provide sedation following coronary artery bypass surgery. The need for additional sedation, analgesia and hypotensive agents was assessed at two propofol infusion rates (10 or 25 micrograms/kg/min). Both rates provided clinically satisfactory conditions. There were no differences in the requirements for analgesia or vasodilators between the groups. The higher infusion rate of 25 micrograms/kg/min was associated with a lower requirement for additional sedation but a more frequent need to stop the infusion temporarily to prevent hypotension.

Differences in secondary structure between packaged and unpackaged single-stranded DNA of bacteriophage phi X174 determined by Raman spectroscopy: a model for phi X174 DNA packaging.

The single-stranded packaged genome (ssDNA) of bacteriophage phi X174 is shown by Raman spectroscopy to lack both the ordered phosphodiester backbone and base stacking, which are demonstrated for unpackaged, protein-free ssDNA. In solutions of moderate ionic strength, unpackaged ssDNA contains 36 +/- 7% of deoxyribosyl phosphate groups with conventional B-type backbone geometry [i.e., gauche- and trans orientations, respectively, for the 5'O-P (alpha) and 3'O-P (zeta) torsions], indicative of hairpin formation and intramolecular base pairing. Additionally, the bases of unpackaged ssDNA are extensively stacked. Estimates from Raman band hypochromic effects indicate that unpackaged ssDNA contains approximately 70% of the maximal base stacking exhibited in the linear, double-stranded, replicative form III of phi X174 DNA. Conversely, for the packaged phi X174 genome, ordered (B-type) phosphodiester groups are not present, and only 40% of the base stacking in RFIII DNA is observed. These results are interpreted as evidence that the substantial hairpin-forming potential of ssDNA is eliminated by specific and extensive ssDNA-protein interactions within the phi X174 virion. Comparison of the present results with studies of other packaged single-stranded nucleic acids suggests that proteins of the capsid shell (gpF + gpG + gpH) do not fully account for the conformational constraints imposed on ssDNA of phi X174. Accordingly, we propose a model for ssDNA packaging in which the small basic gpJ protein, which is packaged along with the genome, is involved stoichiometrically in binding to the ssDNA (approximately 90 nucleotides per subunit). The proposed gpJ-DNA interactions could prevent helical hairpin formation, restrict base stacking, and disfavor fortuitous base pairing within the capsid. The present analysis is based upon use of model nucleic acids of known conformation for calibration of the Raman intensity in the region 810-860 cm-1 in terms of specific secondary structures. The calibration curve allows quantitative determination of the percentage of ssDNA nucleotides for which the 5'O-P-O3' group is configured (g-,t) as in the B-form of DNA. The method proposed here is analogous to that employed by Thomas and Hartman (1973) for ssRNA and should be applicable to single-stranded DNA and to partially denatured forms of double- and multiple-stranded DNAs.

Preliminary investigation of the phage phi X174 crystal structure.

Crystals of the single-stranded DNA bacteriophage phi X174 have been grown. They have a monoclinic unit cell with space group P2(1), unit cell dimensions of a = 306.0 (+/- 0.2) A, b = 361.1 (+/- 0.2) A, c = 299.7 (+/- 0.2 degrees) A, beta = 92.91 degrees (+/- 0.02 degrees) and diffract to at least 2.7 A resolution. There are two virus particles per unit cell. Packing considerations show that the mean diameter of the virus particles is 280 A. The virus separates into two bands in a sucrose gradient. The ratio between the absorbance at 260 nm and 280 nm is 1.45 to 1.65 for the faster and 1.15 to 1.35 for the slower bands, but both bands contain intact particles. Crystals derived from these bands are isomorphous and there is no detectable difference in their structure amplitudes.

Analgesia following inguinal herniotomy or orchidopexy in children: a comparison of caudal and regional blockade.

The effectiveness of postoperative analgesia was compared in 44 children undergoing inguinal surgery, 19 of whom received caudal analgesia (1 ml 0.2% bupivacaine/kg) and 25 ilioinguinal block (0.25 ml 0.5% bupivacaine/kg). The requirement for supplementary analgesia (intramuscular morphine) was less in the caudal group, although this did not reach statistical significance in the number studied. Ilioinguinal and caudal blockade both provide useful postoperative analgesia for children following ilioinguinal surgery.

Plasma bupivacaine concentrations during caudal analgesia and ilioinguinal-iliohypogastric nerve block in children.

Plasma bupivacaine concentrations were measured in 27 children aged 3-7 years who received one of two analgesic regimens for herniotomy or orchidopexy. Analgesia was provided either by caudal epidural bupivacaine 0.2% 2 mg/kg (n = 14) or by ilioinguinal-iliohypogastric nerve block with bupivacaine 0.5% 1.25 mg/kg (n = 13). Mean (SD) peak venous bupivacaine concentrations were 0.57 (0.17) microgram/ml and 0.79 (0.38) microgram/ml respectively. Time to peak plasma concentrations were 29.6 (7.9) and 22.3 (10.9) minutes respectively. These concentrations are well below the potentially toxic level of 4.0 micrograms/ml, but suggest that uptake of bupivacaine is more rapid after ilioinguinal-iliohypogastric nerve block than during caudal analgesia.

Anterior fontanelle pressure responses to tracheal intubation in the awake and anaesthetized infant.

In order to define the changes in intracranial pressure which occur during tracheal intubation in young infants, a Ladd transducer was used to monitor anterior fontanelle pressure (AFP) non-invasively in awake (group 1, n = 14) and anaesthetized (group 2, n = 10) infants during intubation of the trachea. Heart rate and systolic arterial pressure were also recorded. In quiet, undisturbed infants, AFP (mean +/- SEM) was similar in groups 1 (9.6 +/- 0.5 mm Hg) and 2 (8.7 +/- 0.8 mm Hg); with crying, AFP increased significantly in both groups. During laryngoscopy in group 1, AFP increased to 33.5 +/- 3.6 mm Hg, which was significantly greater than in the quiet infant, but did not differ significantly from measurements in the crying infant. In group 2, AFP increased significantly to 15.8 +/- 18 mm Hg during laryngoscopy. This increase was significantly less than the group 1 response. Neither heart rate nor systolic arterial pressure changed significantly in either group during laryngoscopy--when compared with measurements in the quiet state. It was concluded that AFP increases significantly during intubation and during crying in the infant. The response to intubation is only partially attenuated by the prior administration of general anaesthesia.

Arterial oxygen saturation following premedication in children with cyanotic congenital heart disease.

To determine the effects of premedication on arterial oxygen saturation (SaO2) and heart rate (HR), 11 children (ages three to seven years) scheduled for elective repair of cyanotic congenital heart defects were studied. Patients were premedicated with oral or rectal pentobarbitone 2 mg.kg-1 90 minutes prior to induction of anaesthesia followed by intramuscular morphine 0.2 mg.kg-1 and atropine 0.02 mg.kg-1 60 minutes prior to induction. The SaO2 and HR of each child were monitored continuously using a Nellcor pulse oximeter during two 90 minute periods: a control period commencing 25.5 hours preoperatively (day 1) and a post premedication period commencing 1.5 hours preoperatively (day 2). Data were compared at time 0 (corresponding to the time of administration of pentobarbitone on day 2), 30 (corresponding to the administration of intramuscular morphine and atropine on day 2), 60 and 90 minutes (the latter corresponding to the time of induction on day 2) after the administration of pentobarbitone. There were no significant differences in SaO2 or HR between day 1 and day 2 at time 0, 60, and 90 minutes. The SaO2 (mean +/- SD) decreased significantly immediately following intramuscular premedication at time 30 minutes on day 2 (72.7 +/- 5.9 per cent) compared to the corresponding time on day 1 (83.9 +/- 2.9 per cent) (p less than 0.05). The duration of this desaturation was 2.5 +/- 1.9 minutes. Heart rate (mean +/- SD) increased from 109.2 +/- 21.3 beats.min-1 at time 30 minutes on day 1 to 142 +/- 20.4 beats.min-1 on day 2 (p less than 0.05). We conclude that administration of intramuscular premedication preceded by oral or rectal pentobarbitone causes transient arterial desaturation and tachycardia in children with cyanotic congenital heart disease.