Early Hypoxia Research Articles

Acute systemic hypoxia elevates venous but not interstitial potassium of dog skeletal muscle

Potassium release through ATP-sensitive potassium (K(ATP)) channels contributes to hypoxic vasodilation in the skeletal muscle vascular bed: It is uncertain whether K(ATP) channels on muscle cells contribute to the process. Potassium from muscle cells must cross the interstitial space to reach the vascular tissues, whereas that from vascular endothelium would have a higher concentration in venous blood than in interstitial fluid. We determined the effect of systemic hypoxia on arterial, venous, and interstitial potassium in the constant-flow-perfused gracilis muscles of anesthetized dogs. Hypoxia reduced arterial Po(2) from 138 to 25 and Pco(2) from 28 to 26 mmHg. Arterial pH and potassium were well correlated (r(2) = 0.9): Both increased in early hypoxia and decreased during the postcontrol. In denervated muscles, perfusion pressure decreased from 95 to 76 mmHg by the end of the hypoxic period; neither venous nor interstitial potassium was elevated. In innervated muscles, perfusion pressure increased from 110 to 172 mmHg by the 11th min of hypoxia and then decreased to 146 mmHg by the end of the hypoxic period; venous potassium increased from 5.0 to 5.3 mM, but interstitial potassium remained unchanged. Glibenclamide abolished both the increase in venous potassium and the hypoxic vasodilation in the innervated muscle. Thus skeletal muscle cells were unlikely to have contributed to the release of potassium, which was suggested to originate from vascular endothelium. The sympathetic nerve supply may play a direct or indirect role in the opening of K(ATP) channels under hypoxic conditions.

P.5.082 Gender differences in the effect ofnootropic medicine, noopept, in the model of early postnatal hypoxia

P.5.082 Gender differences in the effect ofnootropic medicine, noopept, in the model of early postnatal hypoxia

Dynamic changes of gene expression in hypoxia-induced right ventricular hypertrophy.

Hypobaric hypoxia induces right ventricular hypertrophy. The relative contribution of pulmonary hypertension, decreased arterial oxygen, and neuroendocrine stimulation to the transcriptional profile of hypoxia-induced right ventricular hypertrophy is unknown. Whereas both ventricles are exposed to hypoxia and neuroendocrine stimulation, only the right ventricle is exposed to increased load. We postulated that right ventricular hypertrophy would reactivate the fetal gene transcriptional profile in response to increased load. We measured the expression of candidate genes in the right ventricle of rats exposed to hypobaric hypoxia (11% O(2)) and compared the results with the left ventricle. Hypoxia induced right ventricular hypertrophy without fibrosis. In the right ventricle only, atrial natriuretic factor transcript levels progressively increased starting at day 7. Metabolic genes were differentially regulated, suggesting a substrate switch from fatty acids to glucose during early hypoxia and a switch back to fatty acids by day 14. There was also a switch in myosin isogene expression and a downregulation of sarcoplasmic/endoplasmic ATPase 2a during early hypoxia, whereas later, both myosin isoforms and SERCA2a were upregulated. When the right and left ventricle were compared, the transcript levels of all genes, except for myosin isoforms and pyruvate dehydrogenase kinase-4, differed dramatically suggesting that all these genes are regulated by load. Our findings demonstrate that hypoxia-induced right ventricular hypertrophy transiently reactivates the fetal gene program. Furthermore, myosin iso-gene and pyruvate dehydrogenase kinase-4 expression is not affected by load, suggesting that either hypoxia itself or neuroendocrine stimulation is the primary regulator of these genes.

Maternal Serum and Umbilical Cord Blood Leptin Concentrations With Fetal Growth Restriction

In Brief OBJECTIVE To ascertain whether fetal growth restriction is associated with alterations of leptin concentrations in umbilical cord blood and maternal serum. METHODS Maternal serum and umbilical cord blood leptin concentrations were determined by immunoradiometric assay at term in 43 women with uncomplicated singleton pregnancies (group A) and in 27 women with singleton pregnancies complicated by fetal growth restriction (group B), all with normal pregravid body mass index (BMI). RESULTS Maternal serum leptin concentrations were significantly higher in group B compared with group A (45.0 ng/mL [range 34.2–54.9] versus 29.0 ng/mL [range 24.7–33.3]; P < .01). Umbilical cord blood leptin levels were significantly lower in group B compared with group A (8.4 ng/mL [range 3.6–13.2] versus 13.1 ng/mL [9.7–16.5]; P < .01). Maternal serum leptin levels were not significantly correlated with maternal BMI or with neonatal birth weight in either group. Umbilical cord blood leptin concentrations were significantly correlated with neonatal birth weight in both groups. CONCLUSION Growth restricted fetuses at term show umbilical cord blood leptin concentrations significantly lower than those in normal fetuses, suggesting that fetal adipose tissue is a major source of leptin. Maternal serum leptin concentrations are higher in the presence of a growth restricted fetus. This increase might be due to an intrinsic placental mechanism, by which small placentas produce more leptin as a compensatory mechanism, or to early hypoxia. Umbilical cord blood leptin concentrations are lower and maternal serum leptin levels are higher in pregnancies with growth restricted fetuses than in those with normal fetuses.

Maternal serum and umbilical cord blood leptin concentrations with fetal growth restriction.

To ascertain whether fetal growth restriction is associated with alterations of leptin concentrations in umbilical cord blood and maternal serum. Maternal serum and umbilical cord blood leptin concentrations were determined by immunoradiometric assay at term in 43 women with uncomplicated singleton pregnancies (group A) and in 27 women with singleton pregnancies complicated by fetal growth restriction (group B), all with normal pregravid body mass index (BMI). Maternal serum leptin concentrations were significantly higher in group B compared with group A (45.0 ng/mL [range 34.2-54.9] versus 29.0 ng/mL [range 24.7-33.3]; P<.01). Umbilical cord blood leptin levels were significantly lower in group B compared with group A (8.4 ng/mL [range 3.6-13.2] versus 13.1 ng/mL [9.7-16.5]; P<.01). Maternal serum leptin levels were not significantly correlated with maternal BMI or with neonatal birth weight in either group. Umbilical cord blood leptin concentrations were significantly correlated with neonatal birth weight in both groups. Growth restricted fetuses at term show umbilical cord blood leptin concentrations significantly lower than those in normal fetuses, suggesting that fetal adipose tissue is a major source of leptin. Maternal serum leptin concentrations are higher in the presence of a growth restricted fetus. This increase might be due to an intrinsic placental mechanism, by which small placentas produce more leptin as a compensatory mechanism, or to early hypoxia.

Regulation of Hypoxia-inducible Factor-1α Protein Level during Hypoxic Conditions by the Phosphatidylinositol 3-Kinase/Akt/Glycogen Synthase Kinase 3β Pathway in HepG2 Cells

Hypoxia initiates an intracellular signaling pathway leading to the activation of the transcription factor hypoxia-inducible factor-1 (HIF-1). HIF-1 activity is regulated through different mechanisms involving stabilization of HIF-1alpha, phosphorylations, modifications of redox conditions, and interactions with coactivators. However, it appears that some of these steps can be cell type-specific. Among them, the involvement of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in the regulation of HIF-1 by hypoxia remains controversial. Here, we investigated the activation state of PI3K/Akt/glycogen synthase kinase 3beta (GSK3beta) in HepG2 cells. Increasing incubation times in hypoxia dramatically decreased both the phosphorylation of Akt and the inhibiting phosphorylation of GSK3beta. The PI3K/Akt pathway was necessary for HIF-1alpha stabilization early during hypoxia. Indeed, its inhibition was sufficient to decrease HIF-1alpha protein level after 5-h incubation in hypoxia. However, longer exposure (16 h) in hypoxia resulted in a decreased HIF-1alpha protein level compared with early exposure (5 h). At that time, Akt was no longer present or active, which resulted in a decrease in the inhibiting phosphorylation of GSK3beta on Ser-9 and hence in an increased GSK3beta activity. GSK3 inhibition reverted the effect of prolonged hypoxia on HIF-1alpha protein level; more stabilized HIF-1alpha was observed as well as increased HIF-1 transcriptional activity. Thus, a prolonged hypoxia activates GSK3beta, which results in decreased HIF-1alpha accumulation. In conclusion, hypoxia induced a biphasic effect on HIF-1alpha stabilization with accumulation in early hypoxia, which depends on an active PI3K/Akt pathway and an inactive GSK3beta, whereas prolonged hypoxia results in the inactivation of Akt and activation of GSK3beta, which then down-regulates the HIF-1 activity through down-regulation of HIF-1alpha accumulation.

Effect of acute progestational hypoxia on the content of biogenic amines in the brain of albino rat pups: Peptide correction.

We studied the effect of exposure to acute hypobaric hypoxia in the progestational period on the content of biogenic amines in the brainstem and cerebral cortex in rat pups of different age. The possibility of correcting hypoxia-induced changes with regulatory peptides was evaluated. We found that early antenatal hypoxia disturbs maturation of catecholaminergic systems in the brain. It should be emphasized that the differences from the control varied depending on the age of rat pups. Single intranasal administration of Semax heptapeptides and beta-casomorphine-7 to pregnant females prevented changes in the content of biogenic amines in CNS of the offspring during postnatal ontogeny.

Hypoxic modulation of L-type Ca 2+ channels in inspiratory brainstem neurones: Intracellular signalling pathways and metabotropic glutamate receptors

Brief hypoxia (2 min) enhances the activity of L-type Ca 2+ (Ca L) channels. The effect is due to glutamate release and concomitant stimulation of metabotropic glutamate receptors of the mGLUR1/5 type [22] [S.L. Mironov, D.W. Richter, L-type Ca 2+ channels in inspiratory neurones and their modulation by hypoxia, J. Physiol. 512 (1998) 75–87.]. Besides increasing single channel activity, hypoxia induces a negative shift of the activation curve and slows down the inactivation of the Ca L current. In the present study we investigated these effects further, aiming to reveal intracellular signalling pathways that mediate the coupling between mGLURs and Ca L channels. Channel activity was recorded in cell-attached patches from inspiratory brainstem neurones of neonatal mice (P6–11). Ca L channels were inhibited by the mGluR2/3 agonists. mGluR1/5 agonists accelerated and mGluR2/3 agonists suppressed the respiratory output, and correspondingly modified the hypoxic response of the respiratory center. Ca L channels were also modulated by protein kinase C, but this did not prevent the hypoxic modification of channel activity. G-protein activators enhanced and G-protein inhibitors suppressed the Ca L channel activity, and in the presence of these agents the effects of hypoxia were abolished. Ryanodine but not thapsigargin inhibited the channel activity and occluded the hypoxic potentiation. Only G-protein-specific agents and ryanodine prevented the slowing down of inactivation induced by hypoxia. Our data indicate that coupling between mGluR1/5 and Ca L channels is mediated by pathways that utilize G-proteins and ryanodine receptors. Glutamate release and concomitant activation of Ca L channels are responsible for accelerating of respiratory rhythm during early hypoxia.

Characterizing edema associated with cortical contusion and secondary insult using magnetic resonance spectroscopy.

It is traditionally believed that edema associated with brain contusion is vasogenic. The objective of this study was to quantify and characterize the edema in cortical contusion coupled with early hypoxia and hypotension. Sprague-Dawley rats were randomised into six groups: Sham, Trauma moderate (Tm), Trauma severe (Ts), Hypoxia and Hypotension (HH), Tm and Ts with HH (THHm; THHs). Trauma was induced with controlled cortical impact; associated secondary insults lasted 30 minutes. Water content was measured using tissue longitudinal relaxation time (T1). Apparent diffusion coefficient of water (ADC) was calculated from diffusion-weighted imaging and single voxel spectroscopy. In the trauma groups ICP increased at 30 minutes post trauma (p < 0.05) and then gradually decreased. Only in the THH groups, ICP showed a trend to continually rise. No ICP variations were seen in the others groups. The increase in water content at 4 hours post trauma was inversely related to ADC variation (p < 0.0001). A significant increase in water content with low ADC, developed in the injured region in Ts, THHm (p < 0.05) and THHs (p < 0.01) compared to Sham. Intracellular water rose in the whole brain in THH groups although more severely in the THHs (p < 0.01). Immediately after trauma ADC fell in the THH groups, but gradually increased in the THHm, whereas there was no recovery in THHs. The results indicate that the type of edema in the injured area, with and without superimposed secondary insult, is predominantly cytotoxic (cellular). Moreover, secondary insults act synergistically with focal injury to increase cellular water in both injured tissue and remote regions.

Early hypoxia modulates the phenotype of dopaminergic cells in rat di- and mesencephalic cell cultures and induces a higher vulnerability of non-dopaminergic neurons to a second hypoxic exposure

To investigate long-term effects of hypoxia on a cellular level, di- and mesencephalic cell cultures were exposed to hypoxia on in vitro day 2 (incubation in culture medium, pO 2=10–20 mmHg, 24 h) and on in vitro day 13 (incubation in an electrolyte solution, pO 2=10–20 mmHg, 8 h). The numbers of neuron-specific enolase immuno-reactive (NSE-IR) and tyrosine hydroxylase immuno-reactive (TH-IR) neurons and the levels of dopamine, its main metabolites and the spontaneous and potassium-stimulated DA release were determined on DIV 15. Hypoxia on DIV 2 did not affect the numbers of NSE-IR and TH-IR neurons, but increased the dopamine content and dopamine release by about 100% in both di-and mesencephalic cultures. In addition, this hypoxia increased the vulnerability of non-TH-IR neurons to the second hypoxic episode applied during more advanced stages of the culture development on DIV 13. On the contrary, hypoxia exposure did not affect the vulnerability of TH-IR cells.

The effect of carotid sinus denervation on fetal heart rate variation in normoxia, hypoxia and post-hypoxia in fetal sheep.

To investigate whether carotid sinus nerve reflexes are linked to the increase in heart rate variation in acute (one hour) hypoxia in late gestation fetal sheep Comparison of short term variation between intact and carotid sinus denervated fetuses in normoxia, hypoxia and post-hypoxia. Sixteen chronically catheterised pregnant sheep in late gestation. There was no significant difference in short term variation between intact and denervated fetuses in normoxia. In intact fetuses short term variation increased significantly in hypoxia. In denervated fetuses it tended to increase in hypoxia, but this was not statistically significant. During the post-hypoxia period, short term variation increased significantly in denervated fetuses, although at this time it was decreasing in intact fetuses. When the decrease in pH was small intact fetuses showed a significantly greater increase in short term variation than denervated fetuses in hypoxia. In contrast, short term variation increased similarly in both groups when the pH decrease was greater (> 0.03 in early hypoxia and > 0.05 in late hypoxia). Carotid sinus nerve reflexes have an important influence on heart rate variation in hypoxia and post-hypoxia. It appears that other mechanisms (e.g. a rise in circulating catecholamines) are linked to an increase in heart rate variation when mild acidemia occurs in hypoxia.

Haemoglobin is inversely related to plasma lactate and heart rate in the newborn piglet.

It has been hypothesized that an increased level of plasma lactate (La), the product of anaerobic glycolysis, may identify infants with anaemia and early tissue hypoxia. In the newborn piglet, a frequently used model in experimental neonatology, there is a substantial decrease in haemoglobin (Hb) during the first days of life. We have investigated whether a low level of Hb is associated with an increased level of La in the newborn piglet. Arterial blood gas, Hb, glucose, La, and continuous blood pressure and heart rate (HR) recordings were obtained from 66 newborn piglets. In 4 additional piglets recordings were obtained before isovolemic anaemia, during isovolemic anaemia, and after retransfusion of packed red cells. A low concentration of Hb in the newborn piglet correlates with an increased level of La as well as with an increased HR. A reduction of Hb causes an increase in La and in HR. We hypothesize that increased La and increased HR are caused by mild hypoxia due to normal, low Hb levels in the apparently healthy, resting newborn piglet.

Acute hypoxic ventilation, carotid body cell division, and dopamine content during early hypoxia in rats

In a previous study, we showed that the acute hypoxic ventilatory response was blunted in anesthetized chronically hypoxic rats and was restored by blockade of the dopamine D2 receptor with domperidone. We now report observations made during 1-8 days of exposure to 10% O2 on the acute hypoxic ventilatory response and the effect of domperidone and relate them to dopamine content and cellular proliferation in the carotid body. Hypoxic exposure caused a parallel shift in the hypoxic response curve to higher levels of ventilation and arterial oxygen saturation. The greatest response occurred on day 1 and was unaffected by domperidone: dopamine content diminished and mitotic activity increased. By 8 days, hypoxic ventilation approached normal and was significantly augmented by domperidone; in the carotid body, dopamine levels had risen above the control level and mitoses had diminished. Thus the increase in ventilation was inversely related to carotid body dopamine content, which was depressed. The possibility of a causal relationship is discussed.

Does Sleep Enhance the Effect of Subanesthetic Isoflurane on Hypoxic Ventilation?

After surgery, patients may receive little audiovisual stimulation and may sleep. Lack of audiovisual stimulation enhances the suppression of the hypoxic ventilatory response (HVR) by 0.1 minimum alveolar anesthetic concentration (MAC) isoflurane. Sleep also reduces the HVR and may thus increase the risk of hypoxia in patients at this time. We therefore measured the ventilatory response in volunteers to a sustained step hypoxic stimulus (mean arterial oxygen saturation [SaO2] 80% [SEM 0.3] for 20 min) in the presence of 0.1 MAC isoflurane, with subjects in the awake and asleep states. The behavioral states were studied in random order in nine male subjects. The combination of isoflurane and sleep significantly reduced (P < 0.05) normoxic ventilation (6.71 [0.39] vs 8.24 [0.29] L/min) and increased end-tidal PCO2 (PETCO2) (43.1 [0.5] vs 40.4 [0.8] mm Hg) compared with the awake state. However, ventilation was similar in the asleep and awake states during early (15.10 [1.35] vs 15.50 [1.61] L/min) and late (10.45 [0.97] vs 11.03 [0.99] L/min) hypoxia in the presence of isoflurane. Thus sleep did not reduce ventilation during hypoxia in the presence of isoflurane sedation. The increase in PETCO2 during sleep may have offset suppression of the HVR.

Effect of glucocorticoids on collagen accumulation in pulmonary vascular remodeling in the rat.

Administration of corticosteroids may attenuate the development of pulmonary hypertension by inhibiting the cell proliferation and protein synthesis that occur in early pulmonary vascular remodeling. However, in vitro studies show that corticosteroids stimulate collagen synthesis in vascular smooth muscle cells, and corticosteroid administration may be deleterious in stimulating collagen deposition. To test whether corticosteroid treatment promotes vascular collagen production in vivo, we administered triamcinolone diacetate to rats exposed to 10% O2 for 3 days and measured pro alpha 1(I) collagen mRNA and the hydroxyproline/protein ratio in the main pulmonary artery. Triamcinolone treatment (12 mg/kg intraperitoneally, once daily for 3 days) reduced mean right ventricular pressure (11 +/- 1 versus 14 +/- 1 mm Hg) and protein content of pulmonary arteries (1.8 +/- 0.1 versus 2.7 +/- 0.1 mg/vessel) (both p < 0.05). However, corticosteroid treatment produced a dose-related increase in pro alpha 1(I) mRNA levels and increased the ratio of hydroxyproline/protein (47 +/- 2 versus 38 +/- 3 micrograms/mg; p < 0.05). Thus, corticosteroid administration ameliorated the increase in pulmonary hypertension in early hypoxia, but increased the proportion of collagen in the vessel wall. Corticosteroid treatment in pulmonary vascular remodeling may be deleterious in increasing the concentration of collagen in the vessel wall.

Effects of an early postnatal hypoxia on the development of spontaneous head movements in rabbits.

The early detection of minor brain dysfunctions resulting from perinatal hypoxia is very important since the prognosis of the affected children can be substantially improved by a prompt treatment. Therefore, this paper deals with the influence of an early postnatal hypoxia on the postnatal development of spontaneous head movements and the influence of the visual system on head movements in normal and hypoxic disturbed ontogenesis. Head movements were recorded in 12 unrestrained spontaneously behaving alert rabbits from 6 litters with the sensor coil technique. One rabbit of each litter was exposed to a single acute hypoxia (FiO2 = 0.05) for 3 h at the 1st day of life. The siblings were regarded as a control group. The most important characteristic of the postnatal development of the head movements is the forming of horizontal saccadic movements during the second postnatal week and their perfection by an increase in mean velocity up to the 20th postnatal day. The early postnatal hypoxia leads to a decrease of the mean velocity of saccadic head movements. But this is only true if the rabbits have open eyes. Blind-folding the rabbits of the control group during the recordings was followed by a decrease of the mean velocity (14th and 20th postnatal day) and the amplitude (at the 20th postnatal day) of the saccadic head movements. In contrast to the non-hypoxic rabbits, blind-folding had no perceptible influence on head movements in hypoxic rabbits until the 3rd postnatal week. Our results suggest that early postnatal hypoxia causes a

Endotoxin enhances hypoxic constriction of rat aorta and pulmonary artery through induction of EDRF/NO synthase

The vascular response to hypoxia in endotoxin (lipopolysaccharide; LPS)-exposed rat pulmonary artery (PA) and thoracic aorta (AO) was investigated and the mechanism of the observed hypoxic responses defined. In isometric tension studies, LPS-treated AO and PA rings, with and without endothelium, demonstrated decreased (P < 0.05) contractile response to phenylephrine (PE EC50), and the dose response was shifted to the right (P < 0.01) compared with non-LPS treated rings. Both vessel types responded to hypoxia with a markedly increased (P < 0.01) and sustained (P < 0.01) constriction when preexposed to LPS. Control non-LPS rings with endothelium intact had a transient vasoconstriction in early hypoxia, which was abolished with removal of the endothelium. N omega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthase, increased the PE EC50 tension in LPS-treated rings, markedly reduced the duration and magnitude of the hypoxic vasoconstriction in LPS-treated rings, and attenuated the transient vasoconstriction seen in endothelium-intact, non-LPS rings (all P < 0.05). L-Arginine reversed the L-NAME effects. Hypoxia decreased guanosine 3',5'-cyclic monophosphate (cGMP) content 54 +/- 4% in all LPS and 33 +/- 4% in the non-LPS intact rings (P < 0.05). L-NAME reduced cGMP content 90 +/- 5% in all LPS rings. Indomethacin inhibited formation of a constriction factor in aortic LPS-treated rings (P < 0.01) that was endothelium dependent and unaffected by the presence of L-NAME.(ABSTRACT TRUNCATED AT 250 WORDS)

Early postnatal hypoxia induces long-term changes in the dopaminergic system in rats.

A rat model of a mild, chronic, early postnatal hypoxia, characterized by long-term consequences in the behavioural outcome, was used to study long-term consequences in the dopaminergic system. Exposure of newborn rats to an early postnatal hypoxia (hypobaric hypoxia, 11 kPa pO2 in the inspiratory air, 2nd-10th day of life, 10 hours daily) brings about the following lasting neurochemical changes: an increased stimulated dopamine release rate from striatum slices by about 30%, an increased low affinity, high capacity dopamine uptake into striatum synaptosomes by about 100%. The critical period to produce an increased release rate of dopamine was estimated as day 2-6 postnatally. There are no long-term changes in the concentration of dopamine and its metabolites and in the tyrosine hydroxylase activity in consequences of this early postnatal hypoxia. Treatment of newborn animals with L-DOPA (10-50 micrograms/g body weight) previous to hypoxia normalizes the DA release rate.

Effects of Hypoxia on Phrenic Neurogram Response to Vagal and Somatic Stimulation in Newborn Rabbits

Effects of 10% O2 on the response of the phrenic neurogram to vagal (VS) and saphenous stimulation (SS) were studied in anesthetized and artificially ventilated newborn (group 1: 1-3 days old, n = 13; group 2: 8-14 days old, n = 14) and adult (group 3, n = 12) rabbits. In all animals during ventilation with 100% O2 or 10% O2 in N2, VS caused a reduction in the expiratory phase (Te). Te shortening in response to SS was unaffected by hypoxia in group 3, and was abolished in group 2. In group 1, only early hypoxia blocked the Te response to SS. The preserved Te response to VS on one hand, and abolished the effects of SS on the other, suggest that blockade of the somatic inputs is due to the age-dependent action of hypoxia in areas distant to the respiratory neurons.

Extracranial complications of severe head injury

In order to define the role of intracranial and extracranial complications in determining outcome from severe head injury, 734 patients from the Traumatic Coma Data Bank were analyzed. Nine classes of intracranial and 13 classes of extracranial complications occurring within the first 14 days after admission were analyzed, while controlling for age, admission Glasgow Coma Scale motor score, early hypoxia or hypotension, and severe extracranial trauma. Outcome for survivors was based on the last recorded Glasgow Outcome Scale score, obtained a median of 521 days after injury. Intracranial complications did not significantly alter outcome for the study group. Of the extracranial complications, pulmonary, cardiovascular, coagulation, and electrolyte disorders occurred most frequently at 2 to 4 days. Infections developed later, peaking at 5 to 11 days. Gastrointestinal, renal, and hepatic complications followed no specific time course. Electrolyte abnormalities were the most frequent occurrence (59% of patients) but did not alter outcome. Pulmonary infections (41%), shock (29%, systemic blood pressure < or = 90 mm Hg for 30 minutes or more), coagulopathy (19%), and septicemia (10%) were significant independent predictors of an unfavorable outcome. Backward-elimination, stepwise logistic regression modeling indicated that the estimated reduction of unfavorable outcome was 2.9% for the elimination of pneumonia, 3.1% for coagulation disturbances, 1.5% for septicemia, and 9.3% for shock. These data suggest that extracranial complications are highly influential in determining the outcome from severe head injury and that significant improvements in outcome in a sizeable proportion of patients could be accomplished by improving the ability to prevent or reverse pneumonia, hypotension, coagulopathy, and sepsis.