Maximizing organs for donation: the potential for ex situ normothermic machine perfusion.

Currently, there is a shortfall in the number of suitable organs available for transplant resulting in a high number of patients on the active transplant waiting lists worldwide. To address this shortfall and increase the utilization of donor organs, the acceptance criteria for donor organs is gradually expanding including increased use of organs from donation after circulatory death. Use of such extended criteria donors and exposure of organs to more prolonged periods of warm or cold ischaemia also increases the risk of primary graft dysfunction occurring. Normothermic machine perfusion (NMP) offers a unique opportunity to objectively assess donor organ function outside the donor body and potentially recondition those deemed unsuitable on initial evaluation prior to implantation in the recipient. Furthermore, NMP provides a platform to support the use of established and novel therapeutics delivered directly to the organ, without the need to worry about potential deleterious 'off-target' side effects typically considered when treating the whole patient. This review will explore some of the novel therapeutics currently being added to perfusion platforms during NMP experimentally in an attempt to improve organ function and post-transplant outcomes.

Real-time noninvasive assessment of pancreatic ATP levels during cold preservation.

31P-NMR spectroscopy was utilized to investigate rat and porcine pancreatic ATP:P(i) ratios to assess the efficacy of existing protocols for cold preservation (CP) in maintaining organ quality. Following sacrifice, rat pancreata were immediately excised or left enclosed in the body for 15 minutes of warm ischemia (WI). After excision, rat pancreata were stored at 6 degrees C to 8 degrees C using histidine-tryptophan-ketoglutarate solution (HTK) presaturated with air (S1), HTK presaturated with O2 (S2), or the HTK/perfluorodecalin two-layer method (TLM) with both liquids presaturated with O2 (S3). 31P-NMR spectra were sequentially collected at 3, 6, 9, 12, and 24 hours of CP from pancreata stored with each of the three protocols examined. The ATP:Pi ratio for rat pancreata exposed to 15 minutes of WI and stored with S3 increased during the first 9 hours of CP, approaching values observed for organs procured with no WI. A marked reduction in the ATP:Pi ratio was observed beyond 12 hours of CP with S3. After 6 hours of CP, the ATP:Pi ratio was highest for S3, substantially decreased for S2, and below detection for S1. In sharp contrast to the rat model, ATP was barely detectable in porcine pancreata exposed to minimal warm ischemia (<15 minutes) stored with the TLM regardless of CP time. We conclude that 31P-NMR spectroscopy is a powerful tool that can be used to (1) noninvasively evaluate pancreata prior to islet isolation, (2) assess the efficacy of different preservation protocols, (3) precisely define the timing of reversible versus irreversible damage, and (4) assess whether intervention will extend this timing.

Synthesis of bioinspired collagen/alginate/fibrin based hydrogels for soft tissue engineering.

Hydrogels based on natural polymers offer a range of properties to mimic the native extracellular matrix, and provide microenvironments to preserve cellular function and encourage tissue formation. A tri-component hydrogel using collagen, alginate and fibrin (CAF) was developed and investigated at three collagen concentrations for application as a functional extracellular matrix analogue. Physical-chemical characterization of CAF hydrogels demonstrated a thermo-responsive crosslinking capacity at physiological conditions with stiffness similar to native soft tissues. CAF hydrogels were also assessed for cytocompatibility using L929 murine fibroblasts, pancreatic MIN6 ß-cells and human mesenchymal stem cells (hMSCs); and demonstrated good cell viability, proliferation and metabolic activity after 7 days of in vitro culture. CAF hydrogels, especially with 2.5% w/v collagen, increased alkaline phosphatase production in hMSCs indicating potential for the promotion of osteogenic activity. Moreover, CAF hydrogels also increased metabolic activity of MIN6 ß-cells and promoted the reconstitution of spherical pseudoislets with sizes ranging between 50 and 150 µm at day 7, demonstrating potential in diabetic therapeutic applications.

Charcot-Marie-Tooth disease: peripartum management of two contrasting clinical cases.

Charcot-Marie-Tooth disease is a rare hereditary motor and sensory demyelinating polyneuropathy with potentially severe and debilitating peripheral symptoms. Respiratory muscles and vertebral anatomy can be affected, both of which may have significant impact on any planned or unplanned anaesthetic intervention during labour. We describe two cases at opposite ends of a wide spectrum of disease severity. The first case illustrates an approach to the management of a mildly affected patient who was permitted to labour normally, but nevertheless needed a detailed antenatal plan in order to allay her anxiety and prepare for potentially complicated labour analgesia and operative delivery. Spontaneous delivery of a healthy infant did not require anaesthetic intervention during labour. The second woman had severe scoliosis and marked respiratory impairment and required non-invasive ventilatory support for one week before scheduled caesarean section. A single-shot spinal anaesthetic was used as a spinal catheter could not be sited. This produced a high block for which a brief period of respiratory assistance was required. Perioperative management and subsequent high dependency care are discussed.

Isolation of the glucuronic acid conjugate of n-hydroxy-4-aminobiphenyl from dog urine and its mutagenic activity.

The glucuronic acid conjugate of N-hydroxy-4-aminobiphenyl (NOH-4-ABP) has been isolated in relatively pure form from the urine of dogs given 4-aminobiphenyl, utilizing molecular size, ion exchange, adsorption, and partition chromatography. This conjugate is an active mutagen in Salmonella typhimurium strains TA1538 and TA98 but not in TA1535 or TA1537. NOH-4-ABP and 4-nitrosobiphenyl are also highly active in TA1538 and TA98 and inactive in TA1535 and TA1537. These observations support the concept that this conjugate is the water-soluble carrier that delivers the active metabolite to the bladder. A substance of identical chromatographic and spectral properties to the conjugate isolated from dog urine has been synthesized in low yield by the direct condensation of NOH-4-ABP with glucuronic acid. This substance yields NOH-4-ABP on dilute acid hydrolysis. Sodium (N-4-biphenylhydroxylamino-beta-D-glucopyranosid) uronate, the N-O-C isomer, was also synthesized. It was found to have differing chromatographic and chemical properties to the natural conjugate. This evidence suggests that the urinary conjugate is the compound in which conjugation has occurred with the nitrogen atom of the hydroxylamine group rather than the oxygen atom.

Are two (inexperienced) heads better than one (experienced) head? Averaging house officers' prognostic judgments for critically ill patients.

Inexperienced physicians may make prognostic judgments and management decisions about acutely ill patients in the absence of supervision. We hypothesized that mathematically combining judgments of junior and senior house officers might yield aggregate judgments as good as those made by experienced critical care attending physicians. We obtained independent quantitative assessments of the likelihood of in-hospital survival for 269 sequential intensive care unit admissions from the patient's intern or resident and the critical care fellow and attending physician on duty within 24 hours of admission, and compared these judgements with mortality data. By logistic regression, the residents' and fellows' judgments added independent prognostic information to each other (likelihood ratio chi 2, 7.6; df = 1). The junior house officers' and fellows' assessments were significantly less reliable than the attending physicians' by calibration curves, and by Brier scores, 0.126 and 0.127 vs 0.119. All physicians had good discriminating ability (receiver operating characteristic areas [SE] were 0.83 [0.03], 0.85 [0.03], 0.86 [0.03], respectively). A simple average of the residents' and fellows' judgments was slightly but significantly more reliable by calibration curve and by Brier score, 0.117, and as discriminating (ROC area = 0.85, SE = 0.03) as the attending physicians' judgments. Nonmedical studies have shown that averaging independent judgments may compensate for people's tendency to make extreme estimates, and may take advantage of their complementary abilities. This first medical application of this technique suggests that this form of voting by secret ballot may prove useful for health care teams making other judgments and decisions.

Prediction of survival of critically ill patients by admission comorbidity.

The objective of this study was to determine how well the Charlson index of comorbidity would predict mortality of critically ill patients; and how the predictive ability of the index would compare with that of the comorbidity component (Chronic Health Points) of the APACHE II system. This prospective cohort study included in its setting an intensive care unit (ICU) and intermediate ICU (IICU) in a teaching hospital. Patients included a previously assembled inception cohort of 201 patients consecutively admitted to either unit, followed until death or discharge from the hospital, excluding patients admitted after coronary artery bypass grafting, for planned dialysis, or transferred to the IICU from another intensive care unit. Main outcome measures were recorded as death in hospital versus survival at discharge. For each patient we had prospectively obtained all data necessary to predict the probability of in-hospital death using the APACHE II system, and to classify comorbidity using the Charlson index. The Charlson index had significant ability to discriminate between patients who would live and who would die (ROC curve area = 0.67, SE = 0.05). The Chronic Health Points component of APACHE II had no significant discriminating ability (ROC area = 0.57, SE = 0.05), although the full APACHE II system was an excellent predictor (area = 0.87, SE = 0.04). Logistic regression analyses suggested that the Charlson index could contribute significant (p = 0.03) prognostic information to that obtained from the components of APACHE II other than Chronic Health, i.e., acute physiological derangement, age, and reason for admission, but the Chronic Health Points component of APACHE II could not so contribute to the rest of APACHE II (p = 0.19). Our conclusion is that use of the detailed information about comorbidity captured by the Charlson index could improve prognostic predictions even for critically ill patients.

Visual acuity results following treatment of persistent hyperplastic primary vitreous.

The visual acuity outcome of patients with persistent hyperplastic primary vitreous (PHPV) was reviewed. A total of 48 patients with the diagnosis of PHPV were seen at the University of Iowa, Iowa City, from 1971 through 1984. Twenty-five patients were managed nonsurgically, of which 23 had a poor visual acuity outcome (less than or equal to 5/200). Two with mild cases had visual acuities of 20/100 and 20/30. Twenty-three patients were treated surgically. Five of these had no further postoperative rehabilitation. Eighteen patients underwent surgery and aggressive optical and occlusion therapy. Eight of these 18 patients (44%) had postoperative visual acuities of 20/200 or better. These eight patients represent 17% of the study population. Therefore, lensectomy-membranectomy procedures for the purpose of effecting visual development are reasonable therapeutic options in patients with PHPV in whom the findings are primarily anterior in nature, surgery is performed at an early age, and aggressive amblyopia therapy is instituted.

Fluorescein iris angiography. I. Normal pattern.

Fluorescein iris angiography was performed in 42 normal blue or green human eyes to investigate the normal angiographic pattern and in vivo circulation of the iris. Brown irides were unsuitable for the angiography because the brown pigment masked fluorescence. The pattern in the iris was much more complex than in the retina when seen on fluorescein angiography, with interindividual variations in its filling, and these physiological variations may erroneously be considered pathological. Radial arteries of the iris filled rather sluggishly and the circulation in the pupillary and peripupillary region was often much slower than in the peripheral part of the iris. Various segments of the iris usually filled in an irregular order. There was no distinct venous phase, but it merged with the arteriovenous phase. The pupillary region of the iris between the collarette (which contained a fragmented and incomplete minor circle of vessels) and the pupillary margin contained a dense plexus of capillaries. The normal vessels usually showed no fluorescein leakage.

Fluorescein iris angiography. II. Disturbances in iris circulation following strabismus operation on the various recti.

Iris circulation was investigated by fluorescein iris angiography in 33 human eyes before and after tenotomy of one or more recti for correction of strabismus. Tenotomy of one or both horizontal recti produced no appreciable circulatory disturbance in the iris, but tenotomy of superior or inferior rectus produced circulatory delay in superior temporal or inferior temporal sectors, respectively, of the iris. When tenotomies of a horizontal and one or two vertical recti were combined, the defect occurred in the region of the vertical rectus only. Blood supply of the nasal half of the iris was usually not disturbed by tenotomy of the vertical and/or medial rectus. The findings indicate that the blood supply of the iris is segmental and suggest that, in strabismus surgery, cutting the two vertical recti along with the lateral rectus may subject the eye to the risk of anterior segment ischemia. In the light of the present findings, physiological anatomy of the blood supply of the iris and role of the major arterial circle of the iris are discussed.

Isolated inferior oblique paresis.

The clinical features of eight patients with inferior oblique palsy are described and the differential diagnosis discussed. Six of the eight patients were treated by unilateral superior oblique tenotomy; the conditions of all six improved postoperatively.

Persistent hyperplastic primary vitreous: roto-extraction and other surgical experience.

We discuss nine cases of persistent hyperplastic primary vitreous seen recently, including mode of presentation, management and postsurgical follow-up. Emphasis is placed on early operative intervention in order to preserve the globe, as well as to prevent irremedial stimulus deprivation amblyopia. The advantages of roto-extraction in the surgical approach to this entity are considered, and the difficulties of postoperative visual rehabilitation are also discussed.

A curved, hinged ruler for measurement along the globe.

A curved, hinged ruler for measurement along the surface of the globe during strabismus surgery has been designed. A modification of a previously described curved ruler, the current model has a hinge for greater ease of maneuverability and a "T" piece on one end to facilitate measurement and marking of both poles of the muscle without repositioning the ruler.

Evaluation of Jensen procedures by saccades and diplopic fields.

A total of 15 eyes of 13 patients with lateral rectus palsies underwent Jensen procedures; one eye had a medial rectus recession and lateral rectus resection. It was arbitrarily decided to perform a Jensen procedure for patients with less than 40% normal abduction saccadic function. The patients' conditions were evaluated preoperatively and postoperatively by prism cover test. Versions, forced ductions, saccadic velocities, and diplopic field examinations were done. Postoperatively, all patients showed improved saccadic function; 12 of 13 patients acquired a functional range of diplopia-free vision; and 11 of 13 patients had aligned eyes with a good head position. By retrospective analysis we determined that the Jensen procedure gives good results for patients with severe lateral rectus palsy (less than 40% normal saccadic function).

Pursuit is impaired but the vestibulo-ocular reflex is normal in infantile strabismus.

To determine if infantile (congenital) strabismus is associated with a defect of ocular pursuit or vestibulo-ocular reflexes, eye movements were recorded in 14 subjects. Subjects with infantile strabismus had an impairment of temporally directed pursuit when monocularly viewing a moving target. They were unable to normally enhance or cancel the vestibulo-ocular reflex using visual tracking. Vestibulo-ocular reflexes were normal during rotation at 0.3 Hz in the dark. The pursuit defect was not found in subjects with noninfantile strabismus. We suggest that patients with infantile strabismus have a defect of cerebral pursuit control.

Congenital mucocele of the lacrimal sac.

Two infants had congenital mucocele of the lacrimal sac. The diagnosis of this condition was aided by ultrasound. Congenital mucocele is one of the few indications for immediate lacrimal system probing in the neonatal period. Probing in both patients was successful.

Curved ruler for measurement along the surface of the globe.

A curved ruler for measurement along the surface of the globe has been designed to measure the arc instead of the cord measurement. The ruler is especially helpful when one is doing large recessions and posterior fixation of the recti muscles (Faden operation).

Management of monocular congenital cataracts.

From 1971 through 1985, a diagnosis of monocular congenital cataract was made in 14 consecutive patients. All patients had a visually significant cataract that was documented at birth or within 2 months of age. All patients were followed up long enough to report distance linear recognition acuity. Excellent visual acuity (V/A) correlated with earlier surgery, earlier contact lens fit, and excellent amblyopia therapy compliance. The oldest age for attainment of excellent or good V/A was 17 weeks. Patching therapy was based on the binocular fixation pattern. The patching program consisted of 50% occlusion until the age of 2 months and gradually increased to 100% occlusion after the age of 7 months. Six patients (43%) attained excellent V/A (greater than 20/50), with three patients (21%) attaining good V/A (20/60 to 20/100) and five patients attaining poor V/A (less than 20/100).

Surgery for large-angle congenital esotropia. Two vs three and four horizontal muscles.

Large-angle congenital esotropia is usually managed surgically by either of two fundamentally different approaches: (1) the uniform approach, in which surgery is restricted to two extraocular muscles (bimedial recessions or monocular recession-resection), or (2) the selective approach, in which bimedial recessions are combined with resections of one or both lateral rectus muscles. We compared surgical results of the two types of surgery during a ten-year period for 107 patients, of whom 57 underwent bimedial recessions, two had monocular recession-resections, and 48 received three- or four-muscle surgery. The average follow-up time was 2.6 years. The percentage of good surgical results (orthophoria +/- 10 PD) in the selective group was 64.5%, compared with 37.3% in the uniform group. Only three of the 48 patients in the selective group required a second procedure, compared with 17 of 59 patients in the uniform group.

ARDS following acute lithium carbonate intoxication.

Lithium is a two-edged sword; it is on the one hand a unique drug with invaluable psychoactive potential and on the other a drug which can cause multisystem toxicity and even death. We present a case of severe lithium intoxication with multiple organ involvement. Our patient developed the adult respiratory distress syndrome (ARDS), nephrogenic diabetes insipidus (DI), distinctive neurological abnormalities, and hyperglycemia. We believe that this is a case of ARDS due to lithium toxicity in which elevated left atrial pressures were excluded by right heart catheterization and suggest a causal relationship between lithium and ARDS.