Mark E. Finnis

Pantoprazole or Placebo for Stress Ulcer Prophylaxis (pop-up): Randomized Double-blind Exploratory Study*

Objectives:Pantoprazole is frequently administered to critically ill patients for prophylaxis against gastrointestinal bleeding. However, comparison to placebo has been inadequately evaluated, and pantoprazole has the potential to cause harm. Our objective was to evaluate benefit or harm associated with pantoprazole administration. Design:Prospective randomized double-blind parallel-group study. Setting:University-affiliated mixed medical-surgical ICU. Patients:Mechanically ventilated critically ill patients suitable for enteral nutrition. Interventions:We randomly assigned patients to receive either daily IV placebo or pantoprazole. Measurements and Main Results:Major outcomes were clinically significant gastrointestinal bleeding, infective ventilator-associated complication or pneumonia, and Clostridium difficile infection; minor outcomes included overt bleeding, hemoglobin concentration profiles, and mortality. None of the 214 patients randomized had an episode of clinically significant gastrointestinal bleeding, three patients met the criteria for either an infective ventilator-associated complication or pneumonia (placebo: 1 vs pantoprazole: 2), and one patient was diagnosed with Clostridium difficile infection (0 vs 1). Administration of pantoprazole was not associated with any difference in rates of overt bleeding (6 vs 3; p = 0.50) or daily hemoglobin concentrations when adjusted for transfusion rates of packed red cells (p = 0.66). Mortality was similar between groups (log-rank p = 0.33: adjusted hazard ratio for pantoprazole: 1.68 [95% CI, 0.97–2.90]; p = 0.06). Conclusions:We found no evidence of benefit or harm with the prophylactic administration of pantoprazole to mechanically ventilated critically ill patients anticipated to receive enteral nutrition. The practice of routine administration of acid-suppressive drugs to critically ill patients for stress ulcer prophylaxis warrants further evaluation.

Structure and Function of the Kidney in Septic Shock. A Prospective Controlled Experimental Study.

RATIONALE It is unclear how septic shock causes acute kidney injury (AKI) and whether this is associated with histological change. OBJECTIVES We aimed to determine the nature and extent of changes in renal structure and function over time in an ovine model of septic shock. METHODS Fifteen sheep were instrumented with a renal artery flow probe and renal vein cannula. Ten were given intravenous Escherichia coli to induce septic shock, and five acted as controls. Animals were mechanically ventilated for 48 hours, while receiving protocol-guided parenteral fluids and a norepinephrine infusion to maintain mean arterial pressure. Renal biopsies were taken every 24 hours or whenever animals were oliguric for 2 hours. A renal pathologist, blinded to tissue source, systematically quantified histological appearance by light and electron microscopy for 31 prespecified structural changes. MEASUREMENTS AND MAIN RESULTS Sheep given E. coli developed septic shock, oliguria, increased serum creatinine, and reduced creatinine clearance (AKI), but there were no changes over time in renal blood flow between groups (P > 0.30) or over time within groups (P > 0.50). Renal oxygen consumption increased only in nonseptic animals (P = 0.01), but there was no between-group difference in renal lactate flux (P > 0.50). There was little structural disturbance in all biopsies and, although some cellular appearances changed over time, the only difference between septic and nonseptic animals was mesangial expansion on electron microscopy. CONCLUSIONS In an intensive care-supported model of gram-negative septic shock, early AKI was not associated with changes in renal blood flow, oxygen delivery, or histological appearance. Other mechanisms must contribute to septic AKI.

Impact of nasogastric tubes on swallowing physiology in older, healthy subjects: A randomized controlled crossover trial

BACKGROUND & AIMS The presence of a nasogastric tube (NGT) affects swallowing physiology but not function in healthy young adults. The swallowing mechanism changes with increasing age, therefore the impact of a NGT on swallowing in elderly individuals is likely to be different but is not yet known. The aims of this study were to determine the effects of NGTs of different diameter on (1) airway penetration-aspiration, (2) pharyngeal residue, and (3) pharyngeal transit, in older healthy subjects. METHODS Randomized controlled crossover design. Healthy elderly volunteers underwent 3 modified barium swallow studies in which multiple diet and fluid consistencies were swallowed under the following conditions: (A) no NGT (control), (B) fine bore NGT, and (C) wide bore NGT. The control condition was assessed first to establish baseline swallowing function, then NGT order was randomly allocated. RESULTS Of the 15 volunteers (median age 65 years, range 60-81) complete data sets were obtained for 9 (4 with allocation order ABC; 5 with ACB). Wide bore NGT data could not be obtained for 6 volunteers mainly due to tube intolerance. The presence of a NGT was associated with: (i) an increase in airway penetration-aspiration (fine bore NGT with serial liquid swallows and puree) (p < 0.01); (ii) increased pharyngeal residue (p < 0.05) in the pyriform sinus (fine bore NGT with puree); and in the valleculae (both fine and wide bore NGT with soft solids); and (iii) an increase in pharyngeal transit duration regardless of consistency (p < 0.01), with longest swallowing durations with the widest tube. CONCLUSIONS NGT presence increases airway penetration-aspiration, pharyngeal residue and prolongs transit through the pharynx in older healthy individuals. Consideration of NGT impact on swallowing during concurrent oral and enteral feeding is recommended, with further systematic investigation required in elderly patients recovering from critical illness. Clinical trial registry Australia & New Zealand Clinical Trials Registry (ACTRN12613000577718).

Glycaemic control targets after traumatic brain injury: a systematic review and meta-analysis

BackgroundOptimal glycaemic targets in traumatic brain injury (TBI) remain unclear. We performed a systematic review and meta-analysis of randomised controlled trials (RCTs) comparing intensive with conventional glycaemic control in TBI requiring admission to an intensive care unit (ICU).MethodsWe systematically searched MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials to November 2016. Outcomes of interest included ICU and in-hospital mortality, poor neurological outcome, the incidence of hypoglycaemia and infective complications. Data were analysed by pairwise random effects models with secondary analysis of differing levels of conventional glycaemic control.ResultsTen RCTs, involving 1066 TBI patients were included. Three studies were conducted exclusively in a TBI population, whereas in seven trials, the TBI population was a sub-cohort of a mixed neurocritical or general ICU population. Glycaemic targets with intensive control ranged from 4.4 to 6.7 mmol/L, while conventional targets aimed to keep glucose levels below thresholds of 8.4–12 mmol/L. Conventional versus intensive control showed no association with ICU or hospital mortality (relative risk (RR) (95% CI) 0.93 (0.68–1.27), P = 0.64 and 1.07 (0.84–1.36), P = 0.62, respectively). The risk of a poor neurological outcome was higher with conventional control (RR (95% CI) = 1.10 (1.001–1.24), P = 0.047). However, severe hypoglycaemia occurred less frequently with conventional control (RR (95% CI) = 0.22 (0.09–0.52), P = 0.001).ConclusionsThis meta-analysis of intensive glycaemic control shows no association with reduced mortality in TBI. Intensive glucose control showed a borderline significant reduction in the risk of poor neurological outcome, but markedly increased the risk of hypoglycaemia. These contradictory findings should motivate further research.

Occult upper gastrointestinal mucosal abnormalities in critically ill patients

The objectives of this study were to estimate the frequency of occult upper gastrointestinal abnormalities, presence of gastric acid as a contributing factor, and associations with clinical outcomes.

The relationship between the change in central venous pressure and intravenous fluid volume in patients presenting to the emergency department with septic shock

Dear Editor, Previous international guidelines have recommended administering fluid to target central venous pressure (CVP) during the resuscitation phase of acute sepsis [1]; however, studies evaluating CVP as an indicator of volume status have found no clear supporting evidence [2]. Despite the latest Surviving Sepsis Campaign guidelines no longer recommending CVP-guided fluid administration [3], the practice remains widespread [4]. The Australasian Resuscitation In Sepsis Evaluation (ARISE) trial compared early goal-directed therapy (EGDT) with usual care in patients presenting to the emergency department with septic shock [5]. Post hoc analysis of fluid administration, CVP and other haemodynamic data recorded over the first 6 h of the trial provides an opportunity to describe the observed relationship between CVP and fluid administration in a large population of septic patients. The volume of intravenous fluid administered, CVP and mean arterial blood pressure (MAP) recorded during the first 6 h of the ARISE trial were analysed. Patient demographics, therapeutic interventions and outcome were considered as covariates. Delta-CVP (change in CVP between each hour) was plotted against the sum of intravenous fluid administered over each preceding hour (IVT) and delta-MAP (similarly defined). Complete data sets were analysed with no imputation for missing data. Of the 1588 patients randomised in ARISE, 1226 (77.2%) had CVP measured during the first 6 h of resuscitation; 752/792 (94.9%) in the EGDT group and 474/796 (59.5%) in the usual care group. There were 3712 observations for delta-CVP with corresponding IVT recorded (3024 from EGDT group, 688 from usual care group). Median [IQR] IVT was 155 [100, 500] mL and delta-CVP 0 [− 2, 2] mmHg. At all volumes of IVT there was a symmetrical, random scatter of delta-CVP around 0 mmHg, with 95% of observations falling within ± 7 mmHg (Fig. 1a). A between-group difference was seen for the covariates: > 250 and > 500 mL IVT administered in the hour preceding CVP measurement’ [+ 0.39 mmHg (0.19, 0.59), P < 0.01; and + 0.42 mmHg (0.15, 0.69) mmHg, P < 0.01, respectively]; and ‘prior CVP ≥ 10 mmHg’ [mean difference (95% CI) + 0.67 mmHg (0.50, 0.84), P < 0.001]. However, the median [IQR] delta-CVP across these covariates remained unchanged 0 [− 2, 2] mmHg. Delta-CVP and delta-MAP were distributed normally around zero with respect to each other (Fig. 1b). Delta-CVP following fluid resuscitation in sepsis approximates random normal, scattered symmetrically *Correspondence: benjamin.reddi@adelaide.edu.au 1 Intensive Care Unit, Royal Adelaide Hospital, Port Road, Adelaide, SA 5000, Australia Full author information is available at the end of the article

Stress induced hyperglycemia and the subsequent risk of type 2 diabetes in survivors of critical illness

Objective Stress induced hyperglycemia occurs in critically ill patients who have normal glucose tolerance following resolution of their acute illness. The objective was to evaluate the association between stress induced hyperglycemia and incident diabetes in survivors of critical illness. Design Retrospective cohort study. Setting All adult patients surviving admission to a public hospital intensive care unit (ICU) in South Australia between 2004 and 2011. Patients Stress induced hyperglycemia was defined as a blood glucose ≥ 11.1 mmol/L (200 mg/dL) within 24 hours of ICU admission. Prevalent diabetes was identified through ICD-10 coding or prior registration with the Australian National Diabetes Service Scheme (NDSS). Incident diabetes was identified as NDSS registration beyond 30 days after hospital discharge until July 2015. The predicted risk of developing diabetes was described as sub-hazard ratios using competing risk regression. Survival was assessed using Cox proportional hazards regression. Main Results Stress induced hyperglycemia was identified in 2,883 (17%) of 17,074 patients without diabetes. The incidence of type 2 diabetes following critical illness was 4.8% (821 of 17,074). The risk of diabetes in patients with stress induced hyperglycemia was approximately double that of those without (HR 1.91 (95% CI 1.62, 2.26), p<0.001) and was sustained regardless of age or severity of illness. Conclusions Stress induced hyperglycemia identifies patients at subsequent risk of incident diabetes.

Withholding Stress Ulcer Prophylaxis To Mechanically Ventilated Enterally-Fed Critically Ill Patients Appears Safe: A Randomised Double-Blind Placebo Controlled Pilot Study

Acid-suppressing drugs are routinely prescribed to mechanically ventilated patients for prophylaxis against stress ulceration, but there is a lack of recent data to support this strategy.

A Quality Control Study of the Adherence to Recommended Physiological Targets for the Management of Brain-Dead Organ Donors in South Australian Intensive Care Units

Background: The Australian and New Zealand Intensive Care Society and the Australasian Transplant Coordinators Association provide recommendations on the physiological management of brain-dead donors. Problem statement: How often physiological targets are prescribed for brain-dead donors in Australian intensive care units (ICUs), and how well these compare to recommended targets is unknown. It is also unknown how often recommended targets are achieved, irrespective of prescribed targets. Methods: We performed a retrospective, observational quality control study in 81 adult (>18 years) brain-dead donors to describe how often physiological targets were prescribed, comparing these to current guidelines. We determined the proportion of observations within the recommended target range, irrespective of any prescribed target. We aimed to identify poor adherence to recommended targets to guide future quality improvement initiatives. Outcomes: Seventy-four (91%) donors had at least 1 prescribed physiological target written on the ICU chart, with a median of 2 (range 2-5), and a maximum of 13 targets. Prescribed targets appeared to adhere well with recommended targets. Most recommended physiological targets were met irrespective of any prescribed target. However, one-quarter of serum sodium observations and one-third of blood glucose levels were above the recommended target. Implications for practice: Quality improvement initiatives are required to improve the prescription of physiological targets in brain-dead donors in South Australia. Serum sodium and serum glucose targets were not met. However, this most likely reflects the need for current guidelines to be updated in line with current evidence.

Cerebral metabolic effects of strict versus conventional glycaemic targets following severe traumatic brain injury

BackgroundOptimal glycaemic targets for patients with severe traumatic brain injury remain unclear. The primary objective of this microdialysis study was to compare cerebral metabolism with strict versus conventional glycaemic control.MethodsWe performed a prospective single-centre randomised controlled within-subject crossover study of 20 adult patients admitted to an academic neurointensive care unit with severe traumatic brain injury. Patients underwent randomised, consecutive 24-h periods of strict (4–7 mmol/L; 72–126 mg/dl) and conventional (<10 mmol/L; 180 mg/dl) glycaemic control with microdialysis measurements performed hourly. The first 12 h of each study period was designated as a ‘washout’ period, with the subsequent 12 h being the period of interest.ResultsCerebral glucose was lower during strict glycaemia than with conventional control (mean 1.05 [95% CI 0.58–1.51] mmol/L versus 1.28 [0.81–1.74] mmol/L; P = 0.03), as was lactate (3.07 [2.44–3.70] versus 3.56 [2.81–4.30]; P < 0.001). There were no significant differences in pyruvate or the lactate/pyruvate ratio between treatment phases. Strict glycaemia increased the frequency of low cerebral glucose (< 0.8 mmol/L; OR 1.91 [95% CI 1.01–3.65]; P < 0.05); however, there were no differences in the frequency of critically low glucose (< 0.2 mmol/L) or critically elevated lactate/pyruvate ratio between phases.ConclusionsCompared with conventional glycaemic targets, strict blood glucose control was associated with lower mean levels of cerebral glucose and an increased frequency of abnormally low glucose levels. These data support conventional glycaemic targets following traumatic brain injury.Trial registrationISRCTN, ISRCTN19146279. Retrospectively registered on 2 May 2014.