Timing of onset of gastrointestinal bleeding in the ICU: Protocol for a preplanned observational study.

BACKGROUND: Critically ill patients are at risk of gastrointestinal bleeding, but clinically important gastrointestinal bleeding is rare. The majority of intensive care unit (ICU) patients receive stress ulcer prophylaxis (SUP), despite uncertainty concerning the balance between benefit and harm. For approximately half of ICU patients with gastrointestinal bleeding, onset is early, ie within the first two days of the ICU stay. The aetiology of gastrointestinal bleeding and consequently the balance between benefit and harm of SUP may differ between patients with early vs late gastrointestinal bleeding. METHODS: This is a protocol and statistical analysis plan for a preplanned exploratory substudy of the Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) randomized clinical trial, comparing intravenous pantoprazole (40 mg once daily) with placebo in 3350 acutely ill adult ICU patients. We will describe baseline characteristics and assess the time to onset of the first clinically important episode of GI bleeding accounting for survival status and allocation to SUP or placebo. In addition, we will describe differences in therapeutic and diagnostic procedures used in patients with clinically important gastrointestinal bleeding according to early vs late bleeding and 90-day vital status. CONCLUSIONS: The study outlined in this protocol will provide detailed information on patient characteristics and the timing of onset of gastrointestinal bleeding in the patients enrolled in the SUP-ICU trial. This may provide additional knowledge and incentives for future studies on which patients benefit from SUP.

Stress ulcer prophylaxis in adult intensive care unit patients - a protocol for a systematic review.

BACKGROUND: In the intensive care unit (ICU), stress ulcer prophylaxis with proton pump inhibitors or histamine-2-receptor antagonists is standard of care although gastrointestinal bleeding remains uncommon. It remains unknown whether its use is associated with benefits or harms and the quality of evidence supporting the use of stress ulcer prophylaxis has been questioned. Accordingly, the objective of this systematic review was to critically assess the evidence from randomized clinical trials on the benefits and harms of stress ulcer prophylaxis vs. placebo or no prophylaxis in adult ICU patients. METHODS: We will systematically search for randomized clinical trials in major international databases. Two authors will independently screen and select trials for inclusion, extract data and assess the methodological quality using the Cochrane risk of bias tool. Any disagreement will be resolved by consensus. We will perform conventional meta-analyses using Review Manager, and STATA 15, and we will assess the risk of random errors using Trial Sequential Analysis. Also, we will assess and report the overall quality of evidence for all outcomes according to GRADE. DISCUSSION: The evidence on the benefits and harms of stress ulcer prophylaxis in adult ICU patients is unclear and an updated systematic review is warranted as new trials have been published. To control risks of systematic and random errors, we will use Cochrane and GRADE methodology and Trial Sequential Analysis. Our ambition with this systematic review is to provide updated, reliable and precise data to better inform decision makers on the use of stress ulcer prophylaxis in adult ICU patients.

Development and internal validation of the Simplified Mortality Score for the Intensive Care Unit (SMS-ICU).

BACKGROUND: Intensive care unit (ICU) mortality prediction scores deteriorate over time, and their complexity decreases clinical applicability and commonly causes problems with missing data. We aimed to develop and internally validate a new and simple score that predicts 90-day mortality in adults upon acute admission to the ICU: the Simplified Mortality Score for the Intensive Care Unit (SMS-ICU). METHODS: We used data from an international cohort of 2139 patients acutely admitted to the ICU and 1947 ICU patients with severe sepsis/septic shock from 2009 to 2016. We performed multiple imputations for missing data and used binary logistic regression analysis with variable selection by backward elimination, followed by conversion to a simple point-based score. We assessed the apparent performance and validated the score internally using bootstrapping to present optimism-corrected performance estimates. RESULTS: The SMS-ICU comprises seven variables available in 99.5% of the patients: two numeric variables: age and lowest systolic blood pressure, and five dichotomous variables: haematologic malignancy/metastatic cancer, acute surgical admission and use of vasopressors/inotropes, respiratory support and renal replacement therapy. Discrimination (area under the receiver operating characteristic curve) was 0.72 (95% CI: 0.71-0.74), overall performance (Nagelkerke's R2 ) was 0.19 and calibration (intercept and slope) was 0.00 and 0.99, respectively. Optimism-corrected performance was similar to apparent performance. CONCLUSIONS: The SMS-ICU predicted 90-day mortality with reasonable and stable performance. If performance remains adequate after external validation, the SMS-ICU could prove a valuable tool for ICU clinicians and researchers because of its simplicity and expected very low number of missing values.

Stress ulcer prophylaxis in the intensive care unit trial: detailed statistical analysis plan.

BACKGROUND: In this statistical analysis plan, we aim to provide details of the pre-defined statistical analyses of the Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) trial. The aim of the SUP-ICU trial is to assess benefits and harms of stress ulcer prophylaxis with a proton pump inhibitor in adult patients in the intensive care unit (ICU). METHODS: The SUP-ICU trial is an investigator-initiated, international, multicentre, randomised, blinded, parallel-group trial of intravenously pantoprazole 40 mg once daily vs. placebo in 3350 acutely ill adult ICU patients at risk of gastrointestinal bleeding. The primary outcome measure is 90-day mortality. Secondary outcomes include the proportion of patients with clinically important gastrointestinal bleeding, pneumonia, Clostridium difficile infection or myocardial ischaemia, days alive without life support, serious adverse reactions, 1-year mortality, and a health economic analysis. Two formal interim analyses will be performed. The statistical analyses will be conducted according to the outlined pre-defined statistical analysis plan. The primary analysis will be a logistic regression analysis adjusted for stratification variables comparing the two intervention groups in the intention-to-treat population. In a secondary analysis, we will additionally adjust the primary outcome for potential random differences in baseline characteristics. The conclusion will be based on the intention-to-treat population. CONCLUSION: Stress ulcer prophylaxis is standard of care in ICUs worldwide, but has never been tested in large high-quality randomised placebo-controlled trials. The SUP-ICU trial will provide important high-quality data on the balance between the benefits and harms of stress ulcer prophylaxis in adult critically ill patients.

Use of life support in acutely admitted ICU patients. An international cohort study.

BACKGROUND: Use of life support in intensive care unit (ICU) patients has been associated with increased risk of poor outcome. The prognostic importance of the duration of support is less studied. We assessed the use of life support and the association between its duration and 90-day mortality in a contemporary cohort of acutely admitted adult ICU patients. METHODS: We performed a post-hoc analysis of the SUP-ICU 7-day inception cohort study (n = 1034), which was conducted in 97 ICUs in 11 countries. We included patients with an ICU stay of 3 days or more. We assessed the use of life support during the first 3 days in ICU and the crude and adjusted association between its duration and 90-day mortality using logistic regression analyses. RESULTS: We included 690 patients; their 90-day mortality was 23%. During the first 3 days in ICU mechanical ventilation was used in 65%, vasopressors/inotropes in 57% and renal replacement therapy in 13%. Renal replacement therapy for 3 days or more was associated with a higher 90-day mortality as compared with 1 day of renal replacement therapy [odds ratio 6.5 (95% confidence interval 1.3 to 32.8)]. For mechanical ventilation and vasopressors/inotropes the odds ratios were 2.2 [0.9 to 5.3] and 1.2 [0.5 to 2.6], respectively. CONCLUSIONS: Among acutely admitted adult ICU patients, a higher number of days of renal replacement therapy in the initial ICU stay were associated with increased risk of death within 90 days. We did not observe such an association for mechanical ventilation or vasopressor/inotropic therapy.

Stress ulcer prophylaxis in the intensive care unit: an international survey of 97 units in 11 countries.

BACKGROUND: Stress ulcer prophylaxis (SUP) may decrease the incidence of gastrointestinal bleeding in patients in the intensive care unit (ICU), but the risk of infection may be increased. In this study, we aimed to describe SUP practices in adult ICUs. We hypothesised that patient selection for SUP varies both within and between countries. METHODS: Adult ICUs were invited to participate in the survey. We registered country, type of hospital, type and size of ICU, preferred SUP agent, presence of local guideline, reported indications for SUP, criteria for discontinuing SUP, and concerns about adverse effects. Fisher's exact test was used to assess differences between groups. RESULTS: Ninety-seven adult ICUs in 11 countries participated (eight European). All but one ICU used SUP, and 64% (62/97) reported having a guideline for the use of SUP. Proton pump inhibitors were the most common SUP agent, used in 66% of ICUs (64/97), and H2-receptor antagonists were used 31% (30/97) of the units. Twenty-three different indications for SUP were reported, the most frequent being mechanical ventilation. All patients were prescribed SUP in 26% (25/97) of the ICUs. Adequate enteral feeding was the most frequent reason for discontinuing SUP, but 19% (18/97) continued SUP upon ICU discharge. The majority expressed concern about nosocomial pneumonia and Clostridium difficile infection with the use of SUP. CONCLUSIONS: In this international survey, most participating ICUs reported using SUP, primarily proton pump inhibitors, but many did not have a guideline; indications varied considerably and concern existed about infectious complications.

Stress ulcer prophylaxis in the intensive care unit: is it indicated? A topical systematic review.

UNLABELLED: Stress ulcer prophylaxis (SUP) is regarded as standard of care in the intensive care unit (ICU). However, recent randomized, clinical trials (RCTs) and meta-analyses have questioned the rationale and level of evidence for this recommendation. The aim of the present systematic review was to evaluate if SUP in the critically ill patients is indicated. DATA SOURCES:  MEDLINE including MeSH, EMBASE, and the Cochrane Library. PARTICIPANTS: patients in the ICU. INTERVENTIONS: pharmacological and non-pharmacological SUP. STUDY APPRAISAL AND SYNTHESIS METHODS: Risk of bias was assessed according to Grading of Recommendations Assessment, Development, and Evaluation, and risk of random errors in cumulative meta-analyses was assessed with trial sequential analysis. A total of 57 studies were included in the review. The literature on SUP in the ICU includes limited trial data and methodological weak studies. The reported incidence of gastrointestinal (GI) bleeding varies considerably. Data on the incidence and severity of GI bleeding in general ICUs in the developed world as of today are lacking. The best intervention for SUP is yet to be settled by balancing efficacy and harm. In essence, it is unresolved if intensive care patients benefit overall from SUP. The following clinically research questions are unanswered: (1) What is the incidence of GI bleeding, and which interventions are used for SUP in general ICUs today?; (2) Which criteria are used to prescribe SUP?; (3) What is the best SUP intervention?; (4) Do intensive care patients benefit from SUP with proton pump inhibitors as compared with other SUP interventions? Systematic reviews of possible interventions and well-powered observational studies and RCTs are needed.

Exercise, hormones, and body temperature. regulation and action of GH during exercise.

UNLABELLED: That physical exercise stimulates pituitary GH secretion has been known for forty years, but the underlying mechanisms as well as the physiological significance remain elusive. We have previously shown that the concomitant increase in core temperature is essential for the exercise-induced GH release, inasmuch as exercise performed at 4 C results in a suppression of GH secretion, whereas passive heating constitutes a potent stimulus for GH release. Moreover, studies in normal subjects show that GH stimulates sweat production and evaporative heat loss during heat exposure with and without exercise, whereas GH-deficiency is associated with reduced sweat secretion and increased heat storage during similar conditions. The neurotransmitters involved in GH secretion during exercise remain uncertain; we therefore investigated the putative role of ghrelin, which is a gut-derived endogenous ligand for the GHS receptor. We measured circulating ghrelin levels before during and after submaximal aerobic exercise in healthy subjects and GH-deficient patients. The circulating ghrelin levels were unchanged during and after exercise in all subjects. Growth hormone stimulates lipolysis and lipid oxidation during basal and fasting conditions and we recently investigated whether GH also regulates substrate metabolism during exercise. The design involved GH-deficient patients studied during exercise with and without GH administration as compared to untreated healthy subjects. Growth hormone predominantly stimulated the turnover of free fatty acids in the recovery phase after exercise. CONCLUSIONS: 1) the increase in GH release during exercise is associated with the concomitant increase in body temperature, 2) GH stimulates sweat secretion and heat evaporation during exercise, which seems to be of distinct physiological significance, 3) ghrelin is not involved in exercise-induced GH release, 4) the impact of GH on substrate metabolism during exercise includes increased FFA turnover.

Biomechanical response to acupuncture needling in humans.

During acupuncture treatments, acupuncture needles are manipulated to elicit the characteristic "de qi" reaction widely viewed as essential to acupuncture's therapeutic effect. De qi has a biomechanical component, "needle grasp," which we have quantified by measuring the force necessary to pull an acupuncture needle out of the skin (pullout force) in 60 human subjects. We hypothesized that pullout force is greater with both bidirectional needle rotation (BI) and unidirectional rotation (UNI) than no rotation (NO). Acupuncture needles were inserted, manipulated, and pulled out by using a computer-controlled acupuncture needling instrument at eight acupuncture points and eight control points. We found 167 and 52% increases in mean pullout force with UNI and BI, respectively, compared with NO (repeated-measures ANOVA, P < 0.001). Pullout force was on average 18% greater at acupuncture points than at control points (P < 0.001). Needle grasp is therefore a measurable biomechanical phenomenon associated with acupuncture needle manipulation.

[Reconstruction of upper esophagus after treatment of cancer in the larynx, hypopharynx and upper esophagus]. / Rekonstruktion af øvre esophagus efter behandling af cancer i larynx, hypopharynx og øvre esophagus.

INTRODUCTION: Two new methods of reconstructing the proximal oesophagus after resection of cancer in the larynx, hypopharynx, or proximal oesophagus are examined. MATERIAL AND METHOD: Between 1991 and 1996, 12 patients were operated on after initial irradiation. The reconstructions were done by a microsurgical technique, with eight jejunum transplants and four tubulated radial forearm flaps. The records were reviewed retrospectively. RESULTS: The patients were hospitalised for about a month and were able to swallow soft food three weeks after the operation. Most patients achieved pain palliation and a good swallowing function for a period of three to more than 24 months, until relapse. All patients except two died between five and 21 months after the operation. DISCUSSION AND CONCLUSION: Both techniques give an acceptable swallowing function until relapse. The size of the defect indicates the choice of flap. They are also suitable in such situations as complex fistula formation, congenital atresia, and the after-effects of corrosion.

A study of stiffness protocol as exemplified by testing of a burst fracture model in sagittal plane.

STUDY DESIGN: An in vitro biomechanical study of lumbar spine segments. OBJECTIVE: To study the characteristics of the stiffness test protocol. SUMMARY OF BACKGROUND DATA: In an in vitro study using a flexibility protocol, forces are applied and motions are measured; no center of rotation needs to be specified. In a study using a stiffness protocol, the forces are measured and the motions are applied. This does require the center of rotation to be specified. Many biomechanical studies of the spine are available, but there is lack of clarity concerning which of these two test protocols is appropriate to achieve a certain study goal. METHODS: Five-vertebrae lumbar spine specimens with burst fractures in the middle vertebrae (L1) were used. Specially designed apparatus applied flexion and extension rotations around five centers of rotations located on anteroposterior line through the middle of L1. Maximum moment of 4 Nm was applied. RESULTS: The authors found load-displacement curves, ranges of motion, and neutral zones obtained at the five centers of rotations to be markedly different. The center of rotation located at the posterior longitudinal ligament produced large range of motion and neutral zones in comparison to the centers of rotation located at the anterior longitudinal ligament and the spinous process tip (P<0.01). CONCLUSIONS: The stiffness protocol requires that a center of rotation be specified. Shown here is the significant variability in the load-displacement curves, depending on the choice of the location of the center of rotation. Certain center of rotation locations may block the natural motions of the spine and may result in tissue damage.

Pin loosening in a halo-vest orthosis: a biomechanical study.

STUDY DESIGN: The cranial pin force history of a halo-vest orthosis was measured using an instrumented halo in a clinical study with three patients. Pin force values at the time of halo-vest application and at subsequent clinical visits during the halo-vest wear period were compared. OBJECTIVES: To document the pin force reduction in the cranial pins of a halo-vest orthosis in vivo. SUMMARY OF BACKGROUND DATA: The halo-vest is an orthosis commonly used to immobilize and protect the cervical spine. An important problem with halo-vest use is pin loosening. There have been no previous reports of pin force history in vivo. METHODS: A custom-built strain-gauged, open-ring halo was used to measure the compressive force and superiorly-inferiorly directed shear forces produced at the tips of the two posterior pins. The instrumented halo was applied to three patients with cervical spine fractures. Pin force measurements were recorded at the time of halo application and at subsequent follow-up visits during the entire treatment period. RESULTS: A mean compressive force of 343 +/- 64.6 N was produced at the pin tips during halo application with the patient in a supine position. On average, the compressive forces decreased by 83% (P = 0.002) during the typical halo-vest wear period. The compressive forces were substantially greater than the shear forces, which averaged only -11+/-30.2 N at the time of halo application and which did not change significantly with time. CONCLUSIONS: The study confirmed the hypothesized decrease in the compressive pin forces with time. All patients had developed at least some clinical symptoms of pin loosening at the time of halo-vest removal.

[Sentinel node diagnostics in malignant melanoma]. / "Sentinel node"-diagnostik ved malignt melanom.

New trial have shown that immediate regional lymph node dissection offers increased survival in patients with regional lymph node metastases only. Introduction of isotope technique to identify the first node, the sentinel node (SN), receiving lymph from a tumour area has made it possible to avoid node dissection in SN metastasis negative patients. The feasibility of the technique is illustrated by to examples.

Pin force measurement in a halo-vest orthosis, in vivo.

The halo-vest is an orthosis commonly used to immobilize and protect the cervical spine. The primary complications associated with the halo-vest have been attributed to cranial pin loosening. However, the pin force history during day-to-day halo-vest wear has not previously been reported. This paper presents a new technique developed to monitor cranial pin forces in a halo-vest orthosis, in vivo. A strain gaged, open-ring halo was used to measure the compressive and shear forces produced at the posterior pin tips. The strain gages measured the bending moments produced by these forces without compromising the structural integrity of the halo-vest system. The prototype halo measured the compressive and shear force components with a resolution of +/- 15 and +/- 10 N, respectively. To test the feasibility and durability of the device, it was applied to one patient requiring treatment with a halo-vest orthosis. At the time of halo-vest application, the mean compressive force in the two posterior pins was 368 N. Over the 3 month treatment period, the compressive forces decreased by a mean of 88%. The shear forces were relatively insignificant. Using this technology future work will be aimed at determining the causes of pin loosening, optimizing vest and pin designs, and investigating the safety of more rapid rehabilitation.

Anterior cervical fusion using a modified tricortical bone graft: a radiographic analysis of outcome.

A technique was developed to resist graft extrusion by means of mechanical interlocking between graft and vertebrae. A 4-mm burr is used to create a transverse trough (mortise) across the posterior aspect of each endplate. A reversed tricortical graft is shaped to have a ridge (tenon) composed of cortical bone on the upper and lower surfaces of its posterior portion. The ridges lock into the troughs to form a double mortise and tenon joint. Of 117 discs (102 patients) treated, adequate radiographs were available of 106 discs (in 92 patients) of which 89% were fused at last follow-up. Radiographic analysis showed significant (p < 0.001) increases in disc height and extension immediately postoperatively and a return to the preoperative values by the time of fusion. This technique completely eliminated graft extrusion without any reduction in fusion rate compared with most other reported results with the standard tricortical technique.

Clinical, radiographic, and kinematic results from an adjustable four-pad halovest.

STUDY DESIGN: Charts and radiographs of all patients treated with this halovest at one university hospital were reviewed retrospectively. OBJECTIVES: To describe the outcomes from an adjustable four-pad halovest and to compare them with those from standard halovests, as previously published. SUMMARY OF BACKGROUND DATA: With standard halovests, there can be cervical motion up to 70% of normal values, substantial loads between the halo and vest, and complications of pin loosening, pin infections, and scapular pressure sores. The four-pad vest reduces halovest loads and vest-torso motions. METHODS: The four-pad vest has four independently adjustable pads that completely avoid contact with the scapula, clavicle, and abdomen. Clinical records were analyzed to determine the incidences of halo pin loosening, pressure sores, injury or surgical site nonunion, and loss of cervical alignment. Lateral radiographs were taken with the patient in the upright and supine positions at various times to determine intervertebral rotations (flexion-extension). RESULTS: The clinical results with the four-pad vest were at least as good as those for standard vests. Scapular pressure sores were prevented completely by the absence of vest-scapula contact. Kyphosis did not increase significantly with time. The mean segmental rotations were all 3 degrees or less and showed a smoothly decreasing pattern from C1-C2 to C6-C7. The value at Oc-C1 was opposite to that at C1-C2 and is the subject of further analysis. CONCLUSIONS: The rotations occurring with the four-pad vest are less than or equal to those occurring with standard vests, for overall cervical rotation and for individual motion segment rotations. This is consistent with the smaller halovest forces seen with this vest. Prospective, comparative testing will assess the clinical significance of these findings.

Effect of test environment on intervertebral disc hydration.

STUDY DESIGN: Water content of fresh human lumbar intervertebral discs (with adjacent endplates) was assessed in three studies: 1) after each of seven specimen preparation steps. 2) during exposure to either saline spray or a saline bath, and 3) during exposure to a saline bath and 445 N axial compression, either without or with previous exposure to the bath and no compression ("free swelling"). OBJECTIVE: To assess the effect on disc hydration of various aspects of specimen preparation and testing environments. SUMMARY OF BACKGROUND DATA: Water content is an important determinant of disc behavior. Specimen preparation method and testing environments may be important determinants of water content, yet no work appears to have been reported specifically on this topic. METHODS: Endplate-disc-endplate specimens were prepared from refrigerated cadavers within 24 hours of death by transverse sectioning of adjacent vertebral bodies. Water content change was determined by specimen weight change across each time interval of interest. RESULTS: Specimen preparation (including multiple freeze-thaw cycles) produced no water content change. Saline spray and plastic film wrap resulted in no change, but saline bath exposure resulted in a 24% increase over 7 hours, 44% of which occurred in the first 0.5 hour. A subsequent 7 hours of 445 N compression reduced the overall increase to 10%. This was not significantly different from the 8% increase that resulted from initial exposure to saline bath and compression. CONCLUSIONS: Specimen preparation as typically performed and specimen exposure to saline spray and plastic film wrap do not result in hydration change. Exposure to saline bath results in substantial swelling, which can either be reversed or prevented by axial compression in the physiologic range. Whether discs exposed to saline spray and wrap without compression and those exposed to saline bath with compression behave the same and which of these more closely mimics the in vivo condition are important issues for the experimentalist to test.

[Seal fingers and other infections transmitted from seals]. / Saelfinger og andre infektioner overførbare fra saeler.

Seals and other Pinnipedia my carry a range of infectious agents which could be of clinical interest. A paramyxovirus infection caused epizootic seal death around danish coasts in 1988, but as the population is now recovering more contacts between seal and man must be envisaged. Bites and other forms of direct and indirect contact and carry a risk of development of seal (or blubber) finger. This entity encompasses oedema of the affect finger, swelling of the interphalangeal joint adjacent to the lesion, and no suppuration. The condition is extremely painful and may lead to residual dysfunction or amputation. There is circumstantial evidence that the condition is caused by mycoplasma, and Canadian researchers have identified three species, one of which has been directly linked to blubber finger. At the first medical contact after seal bites and other seal-inflicted lesions thorough cleansing with water and soap is recommended. Systemic therapy with tetracycline is recommended, but both fluorquinolones and macrolides may be efficacious.

A poroelastic finite element formulation including transport and swelling in soft tissue structures.

A field theory is presented for the study of swelling in soft tissue structures that are modeled as poroelastic materials. As a first approximation, soft tissues are assumed to be linear isotropic materials undergoing infinitesimal strains. Material properties are identified that are necessary for the solution of initial boundary value problems where swelling and convection are significant. A finite element model is developed that includes the solid displacements, the relative fluid displacements, and a representative concentration as the primary unknowns. A numerical example is presented based on a triphasic model. The finite model simulates a typical experimental protocol for soft tissue testing and demonstrates the interaction and coupling associated with relative fluid motion and swelling in a deforming poroelastic materiaL The theory and finite element model provide a starting point for nonlinear porohyperelastic transport-swelling analyses of soft tissue structures that include finite strains in anisotropic materials.