Lung ultrasound in diagnosing and monitoring pulmonary interstitial fluid.

Chronic heart failure is a complex clinical syndrome often characterised by recurrent episodes of acute decompensation. This is acknowledged as a major public health problem, leading to a steadily increasing number of hospitalisations in developed countries. In decompensated heart failure, the redistribution of fluids into the pulmonary vascular bed leads to respiratory failure, a common cause of presentation to the emergency department. The ability to diagnose, quantify and monitor pulmonary congestion is particularly important in managing the disease. Lung ultrasound (US) is a relatively new method that has gained a growing acceptance as a bedside diagnostic tool to assess pulmonary interstitial fluid and alveolar oedema. The latest developments in lung US are not because of technological advance but are based on new applications and discovering the meanings of specific sonographic artefacts designated as B-lines. Real-time sonography of the lung targeted to detection of B-lines allows bedside diagnosis of respiratory failure due to impairment of cardiac function, as well as quantification and monitoring of pulmonary interstitial fluid. Lung US saves time and cost, provides immediate information to the clinician and relies on very easy-to-acquire and highly reproducible data.

Clinical application of lung ultrasound in patients with acute dyspnea: differential diagnosis between cardiogenic and pulmonary causes.

This review discusses the usefulness of bedside lung ultrasound in the diagnostic distinction between the various causes of acute dyspnoea in the emergency department, with special attention to the differential diagnosis of pulmonary oedema and exacerbation of chronic obstructive pulmonary disease (COPD). This is made possible by using mid- to low-end scanners and simple acquisition techniques accessible to both radiologists and clinicians. Major advantages include ready availability at the bedside, the absence of ionising radiation, high reproducibility and cost efficiency. The technique is based on the recognition and analysis of sonographic artefacts rather than direct visualisation of the pulmonary structures. These artefacts are caused by the interaction of water-rich structures and air, called comet tails or B-lines. When such artefacts are widely detected on anterolateral transthoracic lung scans, diffuse alveolar-interstitial syndrome can be diagnosed, which is often a sign of acute pulmonary oedema. This condition rules out exacerbation of COPD as the main cause of acute dyspnoea.

Thoracic ultrasonography: a narrative review.

This narrative review focuses on thoracic ultrasonography (lung and pleural) with the aim of outlining its utility for the critical care clinician. The article summarizes the applications of thoracic ultrasonography for the evaluation and management of pneumothorax, pleural effusion, acute dyspnea, pulmonary edema, pulmonary embolism, pneumonia, interstitial processes, and the patient on mechanical ventilatory support. Mastery of lung and pleural ultrasonography allows the intensivist to rapidly diagnose and guide the management of a wide variety of disease processes that are common features of critical illness. Its ease of use, rapidity, repeatability, and reliability make thoracic ultrasonography the "go to" modality for imaging the lung and pleura in an efficient, cost effective, and safe manner, such that it can largely replace chest imaging in critical care practice. It is best used in conjunction with other components of critical care ultrasonography to yield a comprehensive evaluation of the critically ill patient at point of care.

A plea for an early ultrasound-clinical integrated approach in patients with acute heart failure. A proactive comment on the ESC Guidelines on Heart Failure 2016.

BACKGROUND: The European Association of Cardiology (ESC) Guidelines on the diagnosis and treatment of acute heart failure (AHF) indicate prompt therapy initiation and performance of relevant investigations as paramount. Specifically, echocardiography prior to treatment is advocated only with hemodynamic instability, and the evaluation of clinical signs of peripheral perfusion and congestion is suggested as guidance for early interventions. Given the growing body of evidence on the diagnostic/monitoring capabilities of bedside ultrasound (including focused cardiac ultrasound, comprehensive echocardiography, lung ultrasound), we discuss the potential benefit of an integrated clinical/ultrasound approach at the very early stages of acute heart failure. METHODS AND RESULTS: We proposed a narrative review of the current evidence on the clinical-ultrasound integrated approach to AHF, with special emphasis on the components of the early diagnostic-therapeutic workup where cardiac, inferior vena cava and lung ultrasound showed high diagnostic accuracy and the capability of substantially changing an exclusively clinically-oriented patient management. A proactive comment to the ESC guidelines is made, suggesting an integration of clinical and biochemical assessment, as defined by guidelines, with combined bedside ultrasound on may help in the definition of AHF pathophysiology and treatment. CONCLUSION: A multi-organ integrated clinical-ultrasound approach should be advocated as part of the clinical-diagnostic workup at AHF very early phase. Whenever competence and technology available, bedside ultrasound, along with clinical and biochemical assessment, should target AHF profiling, identify the cause of AHF, and subsequently aid disease course and response to treatment monitoring.

The ICM research agenda on critical care ultrasonography.

PURPOSE: Critical care ultrasonography has utility for the diagnosis and management of critical illness and is in widespread use by frontline intensivists. As there is a need for research to validate and extend its utility, the Editor of Intensive Care Medicine included critical care ultrasonography as a topic in the ICM Research Agenda issue. METHODS: Eleven international experts in the field of critical care ultrasonography contributed to the writing project. With the intention of developing a research agenda for the field, they reviewed best standards of care, new advances in the field, common beliefs that have been contradicted by recent trials, and unanswered questions related to critical care ultrasonography. RESULTS: The writing group focused on the provision of training in critical care ultrasonography, technological advances, and some specific clinical applications. CONCLUSIONS: The writing group identified several fields of interest for research and proposed ten research studies that would address important aspects of critical care ultrasonography.

Ultrasonography evaluation during the weaning process: the heart, the diaphragm, the pleura and the lung.

PURPOSE: On a regular basis, the intensivist encounters the patient who is difficult to wean from mechanical ventilatory support. The causes for failure to wean from mechanical ventilatory support are often multifactorial and involve a complex interplay between cardiac and pulmonary dysfunction. A potential application of point of care ultrasonography relates to its utility in the process of weaning the patient from mechanical ventilatory support. METHODS: This article reviews some applications of ultrasonography that may be relevant to the process of weaning from mechanical ventilatory support. RESULTS: The authors have divided these applications of ultrasonography into four separate categories: the assessment of cardiac, diaphragmatic, and lung function; and the identification of pleural effusion; which can all be evaluated with ultrasonography during a dynamic process in which the intensivist is uniquely positioned to use ultrasonography at the point of care. CONCLUSIONS: Ultrasonography may have useful application during the weaning process from mechanical ventilatory support.

Rabbit lens and retina phosphorylate glucose through a glucokinase-like enzyme: study in normal and spontaneously hyperglycemic animals.

After having previously shown that some noninsulin-sensitive tissues (capillaries and optic nerve) phosphorylate glucose in a concentration-dependent manner through a glucokinase-like enzyme, here, we report data on glucose phosphorylation in rabbit lens and retina at various glucose concentrations (1, 5, 10, 25, 50, and 100 mmol/L). In the 3000 g supernatant of lens and retina homogenates from two separate groups of female albino rabbits ten animals in each group; 1.8-2.0 kg body weight; mean +/- SEM morning glycemia: 8.19 +/- 0.28 and 8.12 +/- 0.24 mmol/L, respectively) was assayed glucose phosphorylating activity (NADP reduction measured as change in optical density at 366 nm at pH 7.5). The enzyme activity did not reach the maximum at low glucose concentration (1 mmol/L), as it occurs in several tissues, but increased progressively in both tissues with the increase in glucose concentration. Values (mean +/- SEM) for lens were 0.197 +/- 0.031 nmol/min/mg protein at 1 mmol/L and 0.327 +/- 0.051 (the highest value) at 50 mmol/L glucose (+65.99%, p < 0.01; r = 0.31, p < 0.05). Values for retina were 36.02 +/- 2.12 at 1 mmol/L glucose and 42.48 +/- 2.79 (the highest value) at 25 mmol/L glucose (+17.93%, p < 0.001; r = 0.32, p < 0.05). These kinetic characteristics, somewhat reminiscent of those shown by hepatic glucokinase, are still more pronounced when we calculated the "glucokinase component," obtained by subtracting the activity at 1 mmol/L glucose (hexokinase component) from that at the highest glucose concentration (total glucose phosphorylating activity). In five rabbits of similar age and weight, with spontaneous hyperglycemia (mean +/- SEM morning glycemia: 11.71 +/- 0.60) glucose phosphorylation in the retina was lower than normal, value at pH 7.5 and 1 mmol/L glucose being 24.52 +/- 2.20 versus 36.02 +/- 2.12 of normal animals (-31.93%, p < 0.01). This, if occurs also in other tissues, could contribute to the hyperglycemia by reducing glucose utilization. In these animals, however, the glucose phosphorylating activity retained the responsivity to increasing glucose concentrations, with value at 100 mmol/L of 28.65 +/- 2.10, corresponding to + 16.84% over the value at 1 mmol/L (p < 0.01). Therefore, the actual glucose phosphorylation in the retina of these animals would depend both upon the enzyme level (which is reduced) and glucose concentration (which is increased). Due to the in vivo inhibition of the hexokinase component by glucose 6-phosphate, the glucokinase component in retina and lens may be predominant in vivo, making the stimulating effect of hyperglycemia much more important than it would appear from our in vitro data. This might play a role in the chronic diabetic complications.

[Use of an automatic blood glucose measurement system for the assessment of insulin resistance during the oral glucose tolerance test]. / Utilizzazione di un sistema di controllo automatico della glicemia per la valutazione della insulino-resistenza durante OGTT.

An automatic glycemic control system (Beta-like, Esaote) was used to calculate the insulin area (IA) required to keep glycemia within the normal range during OGTT (using NDDG criteria). IA was calculated by adding total endogenous insulin to insulin infused by the Betalike system (Actrapid HM, Novo). During the test, glycemia was obliged to follow a mean normal curve using an insulin infusion according to a special algorithm which automatically adapted to individual parameter variations during the different stages of OGTT. Fourteen blood samples were collected to assay metabolites (glucose, NEFA, lactate and alanine) and hormones (insulin, C peptide, glucagon). Data on insulinemia and glycemia were used to calculate the respective areas under the total and incremental curve (IA expressed in UL-1 min-1 and GA expressed in mM.L-1.min-1); an insulin resistance index was then calculated (total and incremental) using the following formula: IA/(normal GA/patient GA). This test allows us: a) to evaluate the insulin secretory response to a standard glycemic stimulus represented by a glycemic curve within the normal range; b) to calculate the quantity of insulin necessary to maintain the glycemic curve within the normal range; c) to evaluate the body's total insulin resistance according to an index calculated on the basis of the insulin area required; d) to compare the calculated insulin resistance index with NEFA and glucagon data obtained during the test; e) to identify the exact evolution of these events over time during OGTT.

[Protein S deficiency and thrombophilia: presentation of a clinical case and review of the literature]. / Deficit di proteina S e trombofilia: presentazione di un caso clinico e revisione della letteratura.

We report the case of a 22-year-old obese woman with severe protein S deficiency, probably genetic in nature, associated with recurrent venous thrombosis. Protein S deficiency is a rather rare disease: it may be an inherited, either homozygous (purpura fulminans at neonatal age), heterozygous, or acquired disorder. The thrombophilic state may be manifested as deep vein thrombosis or thrombophlebitis of the superficial veins with a high risk of pulmonary embolism in the young, and it is often exacerbated by pregnancy. In our case, the presenting event, bilateral deep venous (iliac-femoral) thrombosis complicated by disseminated intravascular coagulation, had occurred when the patient was 13 years old. We started long-term therapy with oral coagulants, i.e. warfarin even if the latter may cause skin necrosis ("warfarin dermatitis") in some patients with protein S deficiency. The clinician must consider protein S deficiency in cases of recurrent thrombosis, particularly in young patients: the importance of early implementation of long-term preventive therapy should not be underestimated.

Point-of-care multiorgan ultrasonography for the evaluation of undifferentiated hypotension in the emergency department.

PURPOSE: We analyzed the efficacy of a point-of-care ultrasonographic protocol, based on a focused multiorgan examination, for the diagnostic process of symptomatic, non-traumatic hypotensive patients in the emergency department. METHODS: We prospectively enrolled 108 adult patients complaining of non-traumatic symptomatic hypotension of uncertain etiology. Patients received immediate point-of-care ultrasonography to determine cardiac function and right/left ventricle diameter rate, inferior vena cava diameter and collapsibility, pulmonary congestion, consolidations and sliding, abdominal free fluid and aortic aneurysm, and leg vein thrombosis. The organ-oriented diagnoses were combined to formulate an ultrasonographic hypothesis of the cause of hemodynamic instability. The ultrasonographic diagnosis was then compared with a final clinical diagnosis obtained by agreement of three independent expert physicians who performed a retrospective hospital chart review of each case. RESULTS: Considering the whole population, concordance between the point-of-care ultrasonography diagnosis and the final clinical diagnosis was interpreted as good, with Cohen's k = 0.710 (95 % CI, 0.614-0.806), p < 0.0001 and raw agreement (Ra) = 0.768. By eliminating the 13 cases where the final clinical diagnosis was not agreed upon (indefinite), the concordance increased to almost perfect, with k = 0.971 (95 % CI, 0.932-1.000), p < 0.0001 and Ra = 0.978. CONCLUSIONS: Emergency diagnostic judgments guided by point-of-care multiorgan ultrasonography in patients presenting with undifferentiated hypotension significantly agreed with a final clinical diagnosis obtained by retrospective chart review. The integration of an ultrasonographic multiorgan protocol in the diagnostic process of undifferentiated hypotension has great potential in guiding the first-line therapeutic approach.

Late presentation of ureteral injury following laparoscopic colorectal surgery.

Iatrogenic ureteral injury is an uncommon but dangerous complication of abdominal and pelvic surgery. When recognized and promptly treated, most ureteral lesions heal without sequelae. Instead, undetected injuries may last for a prolonged period of time since symptoms and signs are usually subtle and nonspecific, even if evolution may be life threatening. In doubtful cases the diagnostic role of modern multiphase helical computed tomography is crucial. We describe the late presentation in the Emergency Department of a case of double left ureteral injury after abdominal surgery, and illustrate the appearance of the lesions at computerized tomography.

Controlled oral glucose tolerance test: evaluation of insulin resistance with an insulin infusion algorithm that forces the OGTT glycaemic curve within the normal range. A feasibility study.

This is a technical study to show the feasibility of a computer-controlled oral glucose tolerance test (OGTT) using a specific algorithm, consisting of an OGTT carried out while insulin is infused as required to keep glycaemia within the normal range (National Diabetes Data Group 1979 criteria). This technique allows (a) the amount of insulin (insulin area) required to maintain a normal glycaemic curve to be assessed, a parameter indicating the degree of insulin resistance; and (b) the unique parameter consisting of the insulin secretory response (C-peptide) to a normal glycaemic curve under the inhibitory feedback exerted by the insulin levels required to maintain normal glycaemia to be obtained. Preliminary results confirmed the feasibility of this approach by showing that during the test while the glycaemic area was kept normal the insulinaemic area (endogenous + infused insulin) increased markedly in obese (n = 8) and obese diabetic (n = 5) subjects compared with normal subjects (n = 6), with values of 145.10 +/- 26.71, 204.75 +/- 20.77 and 68.25 +/- 5.93 nmol l-1 min-1 respectively (P < 0.01 in both instances). In contrast, endogenous insulin secretion (C-peptide levels) remained almost unchanged. Compared with data in normal subjects, free fatty acid (FFA) values were basally elevated in the obese and obese diabetic patients, and underwent a smaller decrease during the test. The FFA areas were greater than normal in both groups of patients, suggesting that FFAs were not fully suppressible despite the highest possible insulin levels (higher insulin levels would produce hypoglycaemia). The computer-controlled OGTT might be useful for the metabolic study of patients in the clinical setting.

Insulin sensitivity indices calculated from basal and OGTT-induced insulin, glucose, and FFA levels.

Insulin Sensitivity Indices for glycemia [ISI(gly)] and blood FFA [ISI(ffa)] can be calculated with the formulas: ISI(gly) = 2/[(INSp x GLYp) + 1], and ISI(ffa) = 2/[(INSp x FFAp) + 1], where INSp, GLYp and FFAp = insulinemic, glycemic, and FFA areas during OGTT (75 g glucose) of the person under study, simplified by considering only data at 0 and 2 h (0-2 h areas), according to WHO criteria or, better, at 0, 1 and 2 h (0-1-2 h areas). Expressed as unit/ volume.h-1, 0-1-2 h area is equal to 1/2 value at 0 min + value at 1 h + 1/2 value at 2 h, while 0-2 h area is equal to value at 0 + value at 2 h. Instead of areas, basal levels can also be used. Basal levels and areas are expressed taking the mean normal value as unit, so that in normal subjects ISI(gly) and ISI(ffa) are always around 1, with maximal variations between 0 and 2. Each laboratory should have its normal reference values for basal levels and OGTT areas. However, reliable mean normal values were selected from literature. Based on meta-analysis of published data, ISI(gly) and ISI(ffa) were reduced in subjects who were overweight and/or IGT and in NIDDM patients and their relatives. Moreover, correlation of ISI(gly) with the euglycemic clamp data was significant. However, it should be stressed that the clamp procedure is performed under artificially induced steady-state whereas ISI(gly) and ISI(ffa) are obtained under rather physiological conditions, with hormonal and metabolic variables unmodified, thus being suitable to assess whole-body insulin sensitivity in the clinical setting.

Rabbit optic nerve phosphorylates glucose through a glucokinase-like enzyme: studies in normal and spontaneously hyperglycemic animals.

We investigated glucose phosphorylation at various concentrations of glucose (1, 5, 10, 25, 50, 100 mmol/liter) in rabbit optic nerve. In the 3000 g supernatant of whole rabbit optic nerve homogenates from female albino rabbits (n = 10, 1.8-2.0 kg body weight, mean +/- SEM morning glycemia: 8.25 +/- 0.29 mmol/liter), the glucose phosphorylating activity (NADP reduction measured as change in optical density at 366 nm at pH 7.5) increased progressively with the increase in glucose concentration (r = 0.89; P < 0.05) and approached the maximum at a very high glucose level (100 mmol/liter), with values (mean +/- SEM) of 8.75 +/- 0.97 nanomol/min/mg protein and 11.57 +/- 1.15 at 1 and 100 mmol/liter glucose, respectively (+32.23%; P < 0.01). At a more alkaline pH (8.2; n = 5, mean +/- SEM morning glycemia: 8.83 +/- 0.07 mmol/liter) glucose phosphorylation was higher than at pH 7.5 and retained the glucose concentration dependence (r = 0.95, P < 0.01). These kinetic characteristics are reminiscent of those of the low-affinity enzyme glucokinase, which is typically present in the liver. By subtracting the activity at 1 mmol/liter glucose from that at higher glucose concentrations, we calculated the "glucokinase component," forms the "total" glucose phosphorylating activity. In five rabbits (of similar age and weight) with spontaneous hyperglycemia (mean +/- SEM: 11.71 +/- 0.60 mmol/liter), the optic nerve glucose phosphorylating activity was lower (value at 1 mmol/liter glucose: 5.42 +/- 1.31, -38.06%, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Capillaries phosphorylate glucose in a concentration-dependent manner through a glucokinase-like enzyme: a study in the eel.

Glucose phosphorylation was studied in a pure capillary preparation obtained from the rete mirabile of the eel swimbladder. In the 3000g supernatant of capillary homogenates, the glucose phosphorylating activity did not reach the maximum at low glucose concentration (1 mmole/liter), as it occurs in most tissues, but increased with the increase in glucose concentration and approached the maximum at very high (300 mmole/liter) glucose levels, with values (mean +/- SEM, n = 10) of 5.85 +/- 0.94 nmole.min-1.mg-1 protein and 19.97 +/- 1.89 at 1 and 300 mmole/liter glucose, respectively. The apparent Km value for glucose was about 50 mmole/liter, i.e., at supraphysiological glucose concentration, like the enzyme glucokinase, typically present in the liver but absent from most other tissues. This new enzyme did not phosphorylate fructose (similar to glucokinase from liver, which is rather specific for glucose) but was not inhibited by N-acetyl-glucosamine (in contrast to hepatic glucokinase). Thus, capillaries phosphorylate glucose in a concentration-dependent manner, which suggests that they are equipped with a glucokinase-like enzyme. This may explain the reported increase in glucose uptake during capillary exposure to high glucose concentrations and would suggest that the hyperglycemia of the diabetic state may be associated with increased glucose utilization, which may play a role in the development of microangiopathy.

Metabolic effects of high glucose concentrations: inhibition of hepatic pyruvate kinase.

We tested the in vitro effects of various glucose concentrations on the activity of hepatic pyruvate kinase, assayed at subsaturating, near physiological concentration (0.20 mmol/l) of the substrate phosphoenolpyruvate, to detect the "active" form of the enzyme. A 10-min incubation of mouse liver slices (n = 18) with increasing glucose concentrations (5, 10 and 20 mmol/l) resulted in a significant (p less than 0.01), progressive pyruvate kinase inhibition of 15, 28 and 41%, respectively. Similar data were obtained by incubating mouse liver homogenates (n = 7) with glucose, although with this material (which was supplemented with the pyruvate kinase activator fructose-1,6-diphosphate) the inhibition at the highest glucose concentration used was lower (24%, p less than 0.02). Addition of 10 nmol/l insulin during slice incubation (n = 8) prevented by 98% and 69% the inhibition exerted by 10 and 20 mmol/l glucose, respectively. Insulin alone was without effect on the enzyme activity. Glucose might inhibit pyruvate kinase by competing with the activator fructose-1,6-diphosphate. Insulin might overcome the glucose effect by activating pyruvate kinase through the known mechanism of enzyme dephosphorylation. Thus, in decompensated diabetes the high level of blood glucose may contribute, together with the counterregulatory hormones, to inhibit hepatic pyruvate kinase and therefore to stimulate gluconeogenesis.

A glucokinase-like enzyme carries out glucose phosphorylation in capillaries of normal and spontaneously hyperglycemic rabbits.

We have studied glucose phosphorylation at increasing glucose concentrations (1, 5, 10, 25, 50, and 100 mmol/liter) in capillaries of the choroidocapillary lamina from the eye of normal female albino rabbits (n = 10; body wt 1800-2000 g; mean +/- SEM morning glycemia: 147.77 +/- 4.02 mg/dl) and from the eye of spontaneously hyperglycemic rabbits (n = 5, body wt 1800-2000 g, mean +/- SEM morning glycemia; 211.00 +/- 10.76 mg/dl). In the 3000g supernatant of capillary homogenates, the glucose phosphorylating activity (NADP reduction measured as optical density change at 366 nm at pH 7.5) increased progressively with the rise of glucose concentration (r = 0.36; P < 0.05), approaching the peak at high glucose level (25 mmol/liter), with values ranging from 5.32 +/- 0.46 (SEM) nmol/min/mg protein to 7.14 +/- 0.74 (+34.21%, P < 0.01). When measured at a more alkaline pH (8.2) the glucose phosphorylation was higher than at pH 7.5 and retained the responsiveness to increasing glucose concentrations. These kinetic characteristics differ from those seen in most tissues and are somewhat reminiscent of those shown by hepatic glucokinase. Indeed, by subtracting the activity at 1 mmol/liter glucose from that at higher glucose concentrations, we calculated the "glucokinase component" which together with the "hexokinase component" form the total glucose phosphorylating activity. Glucose phosphorylation in capillaries from spontaneously hyperglycemic rabbits was lower than normal (values: 3.66 +/- 0.31 vs 5.32 +/- 0.46 of the normal rabbits; -31.20%; P < 0.05). This could contribute to the hyperglycemia by reducing glucose utilization. However, in these animals the enzyme activity retained the responsivity to increasing glucose concentrations (r = 0.41, P < 0.05). Therefore, the actual capillary glucose phosphorylation in these animals would depend upon both the enzyme level (which is reduced) and the glucose concentration (which is increased). Due to the in vivo inhibition of the hexokinase component, the glucokinase component may be predominant in vivo, making the stimulating effects of hyperglycemia much more pronounced than it would appear from our data in vitro. This may lead to glucose overutilization. These kinetic characteristics of glucose phosphorylation in capillaries might be relevant to the mechanisms leading to diabetic microangiopathy.

Perinatal mortality in southern Italy.

Perinatal deaths occurring in the Campania region of southern Italy in 1982 were analysed. The perinatal mortality rate was 17.6 per thousand (stillbirth rate 8.3, early neonatal mortality rate 9.3). Compared with Swedish data, our deaths excess does not seem attributable to an unfavourable birthweight distribution, but to high birthweight mortality rates in every birthweight category and particularly in the normal birthweight group (greater than 2500 g). This group of newborns, representing about 94% of the births, contributes 45.4% of perinatal deaths; this situation is not common in developed countries, where the normal birthweight newborns form a much smaller proportion of perinatal deaths. The analysis of the causes of perinatal mortality, even though autopsies are rarely executed in Campania, shows a high prevalence of events which should be prevented by good antenatal and perinatal care.