Disturbed retinoid metabolism upon loss of rlbp1a impairs cone function and leads to subretinal lipid deposits and photoreceptor degeneration in the zebrafish retina.

The RLBP1 gene encodes the 36 kDa cellular retinaldehyde-binding protein, CRALBP, a soluble retinoid carrier, in the visual cycle of the eyes. Mutations in RLBP1 are associated with recessively inherited clinical phenotypes, including Bothnia dystrophy, retinitis pigmentosa, retinitis punctata albescens, fundus albipunctatus, and Newfoundland rod-cone dystrophy. However, the etiology of these retinal disorders is not well understood. Here, we generated homologous zebrafish models to bridge this knowledge gap. Duplication of the rlbp1 gene in zebrafish and cell-specific expression of the paralogs rlbp1a in the retinal pigment epithelium and rlbp1b in Müller glial cells allowed us to create intrinsically cell type-specific knockout fish lines. Using rlbp1a and rlbp1b single and double mutants, we investigated the pathological effects on visual function. Our analyses revealed that rlbp1a was essential for cone photoreceptor function and chromophore metabolism in the fish eyes. rlbp1a-mutant fish displayed reduced chromophore levels and attenuated cone photoreceptor responses to light stimuli. They accumulated 11-cis and all-trans-retinyl esters which displayed as enlarged lipid droplets in the RPE reminiscent of the subretinal yellow-white lesions in patients with RLBP1 mutations. During aging, these fish developed retinal thinning and cone and rod photoreceptor dystrophy. In contrast, rlbp1b mutants did not display impaired vision. The double mutant essentially replicated the phenotype of the rlbp1a single mutant. Together, our study showed that the rlbp1a zebrafish mutant recapitulated many features of human blinding diseases caused by RLBP1 mutations and provided novel insights into the pathways for chromophore regeneration of cone photoreceptors.

A New Zebrafish Model for CACNA2D4-Dysfunction.

Purpose: Mutations in CACNA2D4, encoding the α2δ4 subunit of retinal voltage-gated calcium channels (Cav), cause a rare type of retinal dysfunction in human, mainly affecting cone vision. Here, we investigate the role of CACNA2D4 in targeting of Cav, its influence on cone-mediated signal transmission, and the cellular and subcellular changes upon loss of α2δ4 by exploiting the advantages of the cone-dominant zebrafish as model system. Methods: We identified two zebrafish CACNA2D4 paralogs (cacna2d4a and cacna2d4b), analyzed their expression by RNA in situ hybridization and introduced truncating frameshift mutations through CRISPR/Cas9-mediated mutagenesis. We analyzed retinal function and morphology of the single and double mutant lines by electroretinography, immunohistochemistry, light- and electron microscopy. Results: Knockout of cacna2d4b reduces the expression of Cacna1fa, the pore-forming subunit of retinal Cav1.4, whereas loss of cacna2d4a did not. Only knockout of both paralogs impaired cone-mediated ERG b-wave amplitude. The number of "floating" ribbons is increased in double-KO, while retinal morphology and expression of postsynaptic mGluR6b remain largely unaffected. Both Cacna1fa and Ribeyeb show ectopic punctate expression in cacna2d4b-KO and double-KO photoreceptors. Conclusions: We find that increasing the expression of Cav at the synaptic membrane is an evolutionarily conserved function of Cacna2d4b. Yet, since both paralogs participate in cone synaptic transmission, we propose partial subfunctionalization in zebrafish. Similar to human patients, our double KO zebrafish model shows mild cone dysfunction, which was not associated with signs of retinal degeneration. Therefore, cacna2d4-KO zebrafish is a suitable model to study the pathophysiological mechanisms underlying CACNA2D4 dysfunction in human.

Patient perspectives on intraoperative awareness with explicit recall: report from a North American anaesthesia awareness registry.

BACKGROUND: Awareness during general anaesthesia is a source of concern for patients and anaesthetists, with potential for psychological and medicolegal sequelae. We used a registry to evaluate unintended awareness from the patient's perspective with an emphasis on their experiences and healthcare provider responses. METHODS: English-speaking subjects self-reported explicit recall of events during anaesthesia to the Anesthesia Awareness Registry of the ASA, completed a survey, and submitted copies of medical records. Anaesthesia awareness was defined as explicit recall of events during induction or maintenance of general anaesthesia. Patient experiences, satisfaction, and desired practitioner responses to explicit recall were based on survey responses. RESULTS: Most of the 68 respondents meeting inclusion criteria (75%) were dissatisfied with the manner in which their concerns were addressed by their healthcare providers, and many reported long-term harm. Half (51%) of respondents reported that neither the anaesthesia provider nor surgeon expressed concern about their experience. Few were offered an apology (10%) or referral for counseling (15%). Patient preferences for responses after an awareness episode included validation of their experience (37%), an explanation (28%), and discussion or follow-up to the episode (26%). CONCLUSIONS: Data from this registry confirm the serious impact of anaesthesia awareness for some patients, and suggest that patients need more systematic responses and follow-up by healthcare providers.

Psychological impact of unexpected explicit recall of events occurring during surgery performed under sedation, regional anaesthesia, and general anaesthesia: data from the Anesthesia Awareness Registry.

BACKGROUND: Anaesthetic awareness is a recognized complication of general anaesthesia (GA) and is associated with post-traumatic stress disorder (PTSD). Although complete amnesia for intraprocedural events during sedation and regional anaesthesia (RA) may occur, explicit recall is expected by anaesthesia providers. Consequently, the possibility that there could be psychological consequences associated with unexpected explicit recall of events during sedation and RA has not been investigated. This study investigated the psychological sequelae of unexpected explicit recall of events during sedation/RA that was reported to the Anesthesia Awareness Registry. METHODS: The Registry recruited subjects who self-identified as having had anaesthetic awareness. Inclusion criteria were a patient-reported awareness experience in 1990 or later and availability of medical records. The sensations experienced by the subjects during their procedure and the acute and persistent psychological sequelae attributed to this explicit recall were assessed for patients receiving sedation/RA and those receiving GA. RESULTS: Among the patients fulfilling the inclusion criteria, medical record review identified 27 sedation/RA and 50 GA cases. Most patients experienced distress (78% of sedation/RA vs 94% of GA). Approximately 40% of patients with sedation/RA had persistent psychological sequelae, similar to GA patients. Some sedation/RA patients reported an adverse impact on their job performance (15%), family relationships (11%), and friendships (11%), and 15% reported being diagnosed with PTSD. CONCLUSIONS: Patients who self-reported to the Registry unexpected explicit recall of events during sedation/RA experienced distress and persistent psychological sequelae comparable with those who had reported anaesthetic awareness during GA. Further study is warranted to determine if patients reporting distress with explicit recall after sedation/RA require psychiatric follow-up.

Effect of increasing perfluorocarbon dose on VA/Q distribution during partial liquid ventilation in acute lung injury.

BACKGROUND: Although gas exchange during partial liquid ventilation (PLV) depends on perfluorocarbon liquid, the effect of perfluorocarbon dose on the ventilation-perfusion (VA/Q) distribution is not known. This study investigated how VA/Q distribution of an acutely injured lung is affected during PLV at increasing perfluorocarbon dose. METHODS: In eight rabbits (3.2 +/- 0.1 kg), acute lung injury (ALI) was created by repeated saline lavage (arterial oxygen partial pressure/fraction of inspired oxygen, 37 +/- 11 mm Hg). Three different doses of perfluorodecalin (9 ml/kg = low dose; 13.5 ml/kg = medium dose; 18 ml/kg = functional residual capacity [FRC] dose) were applied in random order during PLV. VA/Q distribution at different doses was evaluated by multiple inert gas elimination technique. RESULTS: Inert gas shunt (63 +/- 21% at ALI) decreased with increasing perfluorocarbon dose (43 +/- 21% at low dose, 29 +/- 10% at medium dose, 11 +/- 9% at FRC dose; P = 0.022). Compared with ALI (0%), the proportion of low VA/Q units was higher at all tested doses (19 +/- 10, 25 +/- 12, and 34 +/- 18%, respectively; all P < 0.05). Compared with ALI (27 +/- 14%), the proportion of normal VA/Q units was not increased at low or medium doses but was increased only at the FRC dose (45 +/- 13%; P = 0.027). CONCLUSIONS: With increasing perfluorocarbon dose during PLV, shunt was reduced from a small dose. The majority shunt units were converted to units showing low VA/Q ratios rather than normal VA/Q ratios. The presence of considerable amount of low VA/Q units across the varying doses of perfluorocarbon suggested that additional measures are necessary during PLV to augment its effect on gas exchange.

Cause-specific mortality risks of anesthesiologists.

BACKGROUND: The health-related effects of the operating room environment are unclear. The authors compared mortality risks of anesthesiologists to those of internal medicine physicians between 1979 and 1995. METHODS: The Physician Master File database, a listing of all US physicians, was used to identify anesthesiologists and general internists. The cohort of internists (n = 40,211) was a stratified random sample of all internists, frequency-matched to the cohort of anesthesiologists (n = 40,242) by gender, decade of birth, and US citizenship. The National Death Index was used to confirm death status and to determine specific causes of death. Mortality risks, adjusted for age, gender, and race, were compared using the Cox proportional hazards regression model. RESULTS: The standardized mortality ratios for all physicians were well below 1.0, except for suicide. The all-cause mortality ratios, and the risks of death caused by cancer and heart disease, did not differ between anesthesiologists and internists. Anesthesiologists had an increased risk of death from suicide (rate ratio [RR] = 1.45, 95% confidence interval [CI] = 1.07 - 1.97), drug-related death (RR = 2.79, 95% CI = 1.87 - 4.15), death from other external causes (RR = 1.53, 95% CI = 1.05 - 2.22), and death from cerebrovascular disease (RR = 1.39, 95% CI = 1.08 - 1.79). Male anesthesiologists had an increased risk of death from HIV (RR = 1.82, 95% CI = 1.09 - 3.02) and viral hepatitis (RR = 7.98, 95% CI = 1.0 - 63.84). Although the risk to anesthesiologists of drug-related deaths was highest in the first 5 years after medical school graduation, it remained increased over that of internists throughout the career. CONCLUSIONS: Substance abuse and suicide represent significant occupational hazards for anesthesiologists. New methods to combat substance abuse among anesthesiologists should be developed.

Anesthesia-related cardiac arrest in children: initial findings of the Pediatric Perioperative Cardiac Arrest (POCA) Registry.

BACKGROUND: The Pediatric Perioperative Cardiac Arrest (POCA) Registry was formed in 1994 in an attempt to determine the clinical factors and outcomes associated with cardiac arrest in anesthetized children. METHODS: Institutions that provide anesthesia for children are voluntarily enrolled in the POCA Registry. A representative from each institution provides annual institutional demographic information and submits anonymously a standardized data form for each cardiac arrest (defined as the need for chest compressions or as death) in anesthetized children 18 yr of age or younger. Causes and factors associated with cardiac arrest are analyzed. RESULTS: In the first 4 yr of the POCA Registry, 63 institutions enrolled and submitted 289 cases of cardiac arrest. Of these, 150 arrests were judged to be related to anesthesia. Cardiac arrest related to anesthesia had an incidence of 1.4 +/- 0.45 (mean +/- SD) per 10,000 instances of anesthesia and a mortality rate of 26%. Medication-related (37%) and cardiovascular (32%) causes of cardiac arrest were most common, together accounting for 69% of all arrests. Cardiovascular depression from halothane, alone or in combination with other drugs, was responsible for two thirds of all medication-related arrests. Thirty-three percent of the patients were American Society of Anesthesiologists physical status 1-2; in this group, 64% of arrests were medication-related, compared with 23% in American Society of Anesthesiologists physical status 3-5 patients (P < 0.01). Infants younger than 1 yr of age accounted for 55% of all anesthesia-related arrests. Multivariate analysis demonstrated two predictors of mortality: American Society of Anesthesiologists physical status 3-5 (odds ratio, 12.99; 95% confidence interval, 2.9-57.7), and emergency status (odds ratio, 3. 88; 95% confidence interval, 1.6-9.6). CONCLUSIONS: Anesthesia-related cardiac arrest occurred most often in patients younger than 1 yr of age and in patients with severe underlying disease. Patients in the latter group, as well as patients having emergency surgery, were most likely to have a fatal outcome. The identification of medication-related problems as the most frequent cause of anesthesia-related cardiac arrest has important implications for preventive strategies.

Regional ventilation-perfusion distribution is more uniform in the prone position.

The arterial blood PO(2) is increased in the prone position in animals and humans because of an improvement in ventilation (VA) and perfusion (Q) matching. However, the mechanism of improved VA/Q is unknown. This experiment measured regional VA/Q heterogeneity and the correlation between VA and Q in supine and prone positions in pigs. Eight ketamine-diazepam-anesthetized, mechanically ventilated pigs were studied in supine and prone positions in random order. Regional VA and Q were measured using fluorescent-labeled aerosols and radioactive-labeled microspheres, respectively. The lungs were dried at total lung capacity and cubed into 603-967 small ( approximately 1.7-cm(3)) pieces. In the prone position the homogeneity of the ventilation distribution increased (P = 0.030) and the correlation between VA and Q increased (correlation coefficient = 0.72 +/- 0.08 and 0.82 +/- 0.06 in supine and prone positions, respectively, P = 0.03). The homogeneity of the VA/Q distribution increased in the prone position (P = 0.028). We conclude that the improvement in VA/Q matching in the prone position is secondary to increased homogeneity of the VA distribution and increased correlation of regional VA and Q.

Airway injury during anesthesia: a closed claims analysis.

BACKGROUND: Airway injury during general anesthesia is a significant source of morbidity for patients and a source of liability for anesthesiologists. To identify recurrent patterns of injury, the authors analyzed claims for airway injury in the American Society of Anesthesiologists (ASA) Closed Claims Project database. METHODS: The ASA Closed Claims database is a standardized collection of case summaries derived from professional liability insurance companies closed claims files. All claims for airway injury were reviewed in depth and were compared to other claims during general anesthesia. RESULTS: Approximately 6% (266) of 4,460 claims in the database were for airway injury. The most frequent sites of injury were the larynx (33%), pharynx (19%), and esophagus (18%). Injuries to the esophagus and trachea were more frequently associated with difficult intubation. Injuries to temporomandibular joint and the larynx were more frequently associated with nondifficult intubation. Injuries to the esophagus were more severe and resulted in a higher payment to the plaintiff than claims for other sites of airway injury. Difficult intubation (odds ratio = 4.53, 95% confidence interval [CI] = 2.36, 8.71), age older than 60 yr (odds ratio = 2.97, 95% CI = 1.51, 5.87), and female gender (odds ratio = 2.43, 95% CI = 1.09, 5.42) were associated with claims for pharyngoesophageal perforation. Early signs of perforation, e.g., pneumothorax and subcutaneous emphysema, were present in only 51% of perforation claims, whereas late sequelae, e.g., retropharyngeal abscess and mediastinitis, occurred in 65%. CONCLUSION: Patients in whom tracheal intubation has been difficult should be observed for and told to watch for the development of symptoms and signs of retropharyngeal abscess, mediastinitis, or both.

Comparative efficacy and safety of ondansetron, droperidol, and metoclopramide for preventing postoperative nausea and vomiting: a meta-analysis.

UNLABELLED: Postoperative nausea and vomiting are important causes of morbidity after anesthesia and surgery. We performed a meta-analysis of published, randomized, controlled trials to determine the relative efficacy and safety of ondansetron, droperidol, and metoclopramide for the prevention of postoperative nausea and vomiting. We performed a literature search of English references using both the MEDLINE database and a manual search. Double-blinded, randomized, controlled trials comparing the efficiency of the prophylactic administration of ondansetron, droperidol, and/or metoclopramide therapy during general anesthesia were included. A total of 58 studies were identified, of which 4 were excluded for methodological concerns. For each comparison of drugs, a pooled odds ratio (OR) with a 95% CI was calculated using a random effects model. Ondansetron (pooled OR 0.43, 95% CI 0.31, 0.61; P < 0.001) and droperidol (pooled OR 0.68, 95% CI 0.54, 0.85; P < 0.001) were more effective than metoclopramide in preventing vomiting. Ondansetron was more effective than droperidol in preventing vomiting in children (pooled OR 0.49; P = 0.004), but they were equally effective in adults (pooled OR 0.87; P = 0.45). The overall risk of adverse effects was not different among drug combinations. We conclude that ondansetron and droperidol are more effective than metoclopramide in reducing postoperative vomiting. IMPLICATIONS: We performed a systematic review of published, randomized, controlled trials to determine the relative efficacy and safety of ondansetron, droperidol, and metoclopramide for preventing postoperative nausea and vomiting. Ondansetron and droperidol were more effective than metoclopramide in reducing postoperative vomiting. The overall risk of adverse effects did not differ.

Awareness during anesthesia: a closed claims analysis.

BACKGROUND: Awareness during general anesthesia is a frightening experience, which may result in serious emotional injury and post-traumatic stress disorder. We performed an in-depth analysis of cases from the database of the American Society of Anesthesiologists Closed Claims Project to explore the contribution of intraoperative awareness to professional liability in anesthesia. METHODS: The database of the Closed Claims Project is composed of closed US malpractice claims that have been collected in a standardized manner. All claims for intraoperative awareness were reviewed by the reviewers to identify patterns of causation and standard of care. Logistic regression analysis was used to identify independent patient and anesthetic factors associated with claims for recall during general anesthesia compared to other general anesthesia malpractice claims. RESULTS: Awareness claims accounted for 79 (1.9%) of 4,183 claims in the database, including 18 claims for awake paralysis, i.e., the inadvertent paralysis of an awake patient, and 61 claims for recall during general anesthesia, ie., recall of events while receiving general anesthesia. The majority of awareness claims involved women (77%), younger than 60 yr of age (89%), American Society of Anesthesiologists physical class I-II (68%), who underwent elective surgery (87%). Most (94%) claims for awake paralysis represented substandard care involving errors in labeling and administration, whereas care was substandard in only 43% of the claims for recall during general anesthesia (P < 0.001). Claims for recall during general anesthesia were more likely to involve women (odds ratio [OR] = 3.08, 95% confidence interval [CI] = 1.58, 6.06) and anesthetic techniques using intraoperative opioids (OR = 2.12, 95% CI = 1.20, 3.74), intraoperative muscle relaxants (OR = 2.28, 95% CI = 1.22, 4.25), and no volatile anesthetic (OR = 3.20, 95% CI = 1.88, 5.46). CONCLUSIONS: Deficiencies in labeling and vigilance were common causes for awake paralysis. Claims for recall during general anesthesia were more likely in women and with nitrous-narcotic-relaxant techniques.

Nerve injury associated with anesthesia: a closed claims analysis.

BACKGROUND: Nerve injury associated with anesthesia is a significant source of morbidity for patients and liability for anesthesiologists. To identify recurrent and emerging patterns of injury we analyzed the current American Society of Anesthesiologists (ASA) Closed Claims Project Database and performed an in-depth analysis of claims for nerve injury that were entered into the database since the authors' initial report of the subject. METHODS: The ASA Closed Claims Database is a standardized collection of case summaries derived from the closed claims files of professional liability insurance companies. Claims for nerve injury that were not included in the authors' 1990 report were reviewed in-depth. RESULTS: Six hundred seventy (16% of 4,183) claims were for anesthesia-related nerve injury. The most frequent sites of injury were the ulnar nerve (28%), brachial plexus (20%), lumbosacral nerve root (16%), and spinal cord (13%). Ulnar nerve (85%) injuries were more likely to have occurred in association with general anesthesia, whereas spinal cord (58%) and lumbosacral nerve root (92%) injuries were more likely to occur with regional techniques. Ulnar nerve injury occurred predominately in men (75%) and was also more apt to have a delayed onset of symptoms (62%) than other nerve injuries. Spinal cord injuries were the leading cause of claims for nerve injury that occurred in the 1990s. CONCLUSION: New strategies for prevention of nerve damage cannot be recommended at this time because the mechanism for most injuries, particularly those of the ulnar nerve, is not apparent.

Positive end-expiratory pressure redistributes perfusion to dependent lung regions in supine but not in prone lambs.

OBJECTIVE: To examine the influence of positive end-expiratory pressure (PEEP) and posture on the distribution of pulmonary blood flow. DESIGN: Experimental study. SETTING: University animal laboratory. SUBJECTS: Seven anesthetized and mechanically-ventilated lambs. INTERVENTIONS: Four conditions were studied in random order: prone or supine position, with or without 5 cm H2O PEEP. MEASUREMENTS AND MAIN RESULTS: The distribution of pulmonary blood flow was assessed using fluorescent-labeled microspheres (15 microm) in small (approximately 1.7 cm3) lung regions. Pulmonary blood flow heterogeneity was evaluated using the coefficient of variation of blood flow of the lung regions. The number of regions analyzed were 1290+/-154 (SD) per animal. PEEP increased pulmonary blood flow heterogeneity in the supine position (47.0+/-7.7% to 54.1+/-7.3%, p < .01, paired Student's t-test), but not in the prone position (40.4+/-8.1% to 39.6+/-11.5). Dorsal to ventral (gravitational) flow gradients were present only in the supine position, and increased with PEEP (-7.2%/cm vs. -10.4% cm, p< .001). CONCLUSIONS: PEEP redistributes pulmonary perfusion to dependent lung regions in supine, but not in prone, anesthetized and mechanically-ventilated sheep.

Effect of high-intensity exercise training on lactate/H+ transport capacity in human skeletal muscle.

The present study examined the effect of high-intensity exercise training on muscle sarcolemmal lactate/H+ transport and the monocarboxylate transporters (MCT1 and MCT4) as well as lactate and H+ release during intense exercise in humans. One-legged knee-extensor exercise training was performed for 8 wk, and biopsies were obtained from untrained and trained vastus lateralis muscle. The rate of lactate/H+ transport determined in sarcolemmal giant vesicles was 12% higher (P < 0.05) in the trained than in untrained muscle (n = 7). The content of MCT1 and MCT4 protein was also higher (76 and 32%, respectively; n = 4) in trained muscle. Release of lactate and H+ from the quadriceps muscle at the end of intense exhaustive knee-extensor exercise was similar in the trained and untrained leg, although the estimated muscle intracellular-to-interstitial gradients of lactate and H+ were lower (P < 0.05) in the trained than in the untrained muscle. The present data show that intense exercise training can increase lactate/H+ transport capacity in human skeletal muscle as well as improve the ability of the muscle to release lactate and H+ during contractions.

Effects of posture on blood flow diversion by hypoxic pulmonary vasoconstriction in dogs.

We used differential excretion of sulphur hexafluoride from the left and right lung to measure blood flow diversion by hypoxic pulmonary vasoconstriction (HPV) in the prone and supine positions in dogs (n = 9). Gas exchange was assessed using the multiple inert gas elimination technique. Blood flow diversion from the hypoxic (3% oxygen) left lung was mean 70.7 (SD 11.2)% in the supine compared with 57.0 (12.1)% in the prone position (P < 0.02). The supine position was associated with increased perfusion to low VA/Q regions (P < 0.05). The increased flow diversion with hypoxia in the supine position was associated with more ventilation to high VA/Q regions (P < 0.05). We conclude that flow diversion by hypoxic pulmonary vasoconstriction is greater in the supine position. This effect could contribute to the variable response in gas exchange with positioning in patients with ARDS.

Pulmonary blood flow does not redistribute in dogs with reposition from supine to left lateral position.

BACKGROUND: Recent studies have questioned the classical gravitational model of pulmonary perfusion. Because the lateral position is commonly used during surgery, the authors studied the redistribution of pulmonary blood flow in the left lateral decubitus position using a high spatial resolution technique. METHODS: Distributions of pulmonary blood flow were measured using intravenously injected 15-microm diameter radioactive-labeled microspheres in eight halothane-anesthetized dogs, which were studied in the supine and left lateral decubitus positions in random order. Lungs flushed free of blood were air-dried at total lung capacity and sectioned into 1,498-2,396 (1.7 cm3) pieces per animal. Radioactivity was measured by a gamma counter, and signals were corrected for piece weight and normalized to mean flow. RESULTS: Blood flow to the dependent left lung did not increase, and blood flow to the nondependent right lung did not decrease in the lateral position. The left lung received 39.3 +/-7.0% and 39.2+/-8.8% (mean +/- SD) of perfusion in the supine and left lateral positions, respectively. Detailed assessment of the spatial distributions of pulmonary blood flow revealed the lack of a gravitational gradient of blood flow in the lateral position. The distributions of blood flow did not differ in the supine and left lateral decubitus positions. CONCLUSIONS: Perfusion to each lung did not change with movement from the supine to the left lateral position. These findings contradict the prediction of increased dependent lung and decreased nondependent lung blood flow based on the gravitational model. It was concluded that the distribution of blood flow in the lateral position in dogs is dominated by pulmonary vascular structure.

Redistribution of pulmonary blood flow during unilateral hypoxia in prone and supine dogs.

We used fluorescent-labeled microspheres in pentobarbital-anesthetized dogs to study the effects of unilateral alveolar hypoxia on the pulmonary blood flow distribution. The left lung was ventilated with inspired O2 fraction of 1.0, 0.09, or 0.03 in random order; the right lung was ventilated with inspired O2 fraction of 1.0. The lungs were removed, cleared of blood, dried at total lung capacity, then cubed to obtain approximately 1,500 small pieces of lung ( approximately 1.7 cm3). The coefficient of variation of flow increased (P < 0.001) in the hypoxic lung but was unchanged in the hyperoxic lung. Most (70-80%) variance in flow in the hyperoxic lung was attributable to structure, in contrast to only 30-40% of the variance in flow in the hypoxic lung (P < 0.001). When adjusted for the change in total flow to each lung, 90-95% of the variance in the hyperoxic lung was attributable to structure compared with 70-80% in the hypoxic lung (P < 0.001). The hilar-to-peripheral gradient, adjusted for change in total flow, decreased in the hypoxic lung (P = 0.005) but did not change in the hyperoxic lung. We conclude that hypoxic vasoconstriction alters the regional distribution of flow in the hypoxic, but not in the hyperoxic, lung.

Pulmonary gas exchange improves in the prone position with abdominal distension.

Arterial blood oxygenation in patients with adult respiratory distress syndrome is often improved in the prone position. Critically ill patients often have abdominal distension and whether similar improvements in gas exchange occur with the prone position is not known. We therefore studied the effect of posture on gas exchange in eight ketamine-anesthetized pigs with abdominal distension. A rubber balloon, placed in the abdominal cavity, was filled with water to increase intra-abdominal pressure. The animals were mechanically ventilated with FIO2 = 0.4, and PaCO2 was kept constant. Gas exchange was measured in the supine and prone positions, with and without abdominal distension, in random order, using the multiple inert gas elimination technique (MIGET). When the abdomen was normal, the prone position increased PaO2 by 16 +/- 21 mm Hg (p < 0.05), accompanied by a small, but statistically insignificant, decrease in AaPO2 (p = 0.08) and no change in ventilation/perfusion (V A/Q) heterogeneity measured by MIGET. In the presence of abdominal distension, the prone position increased Pa O2 by 26 +/- 18 mm Hg (p < 0.01) and decreased AaPO2 (p < 0.05) and V A/Q heterogeneity as measured by the log standard deviation of the perfusion distribution (p < 0.01) and the arterial-alveolar difference area (p < 0.05). In addition, intragastric pressure was lower in the prone position (p < 0.01). We conclude that in anesthetized, mechanically ventilated pigs, the prone position improves pulmonary gas exchange to a greater degree in the presence of abdominal distension than when the abdomen is normal.

Pulmonary blood flow redistribution with low levels of positive end-expiratory pressure.

BACKGROUND: Recent studies have questioned the importance of the gravitational model of pulmonary perfusion. Because low levels of positive end-expiratory pressure (PEEP) are commonly used during anesthesia, the authors studied the distribution of pulmonary blood flow with low levels of PEEP using a high spatial resolution technique. They hypothesized that if hydrostatic factors were important in the distribution of pulmonary blood flow, PEEP would redistribute flow to more dependent lung regions. METHODS: The effects of zero cm H2O PEEP and 5 cm H2O PEEP on pulmonary gas exchange were studied using the multiple inert gas elimination technique; the distribution of pulmonary blood flow, using fluorescent-labeled microspheres, was also investigated in mechanically ventilated, pentobarbital-anesthetized dogs. The lungs were removed, cleared of blood, dried at total lung capacity, and then cubed to obtain approximately 1,000 small pieces of lung (approximately 1.7 cm3). RESULTS: Positive end-expiratory pressure increased the partial pressure of oxygen by 6 +/- 2 mmHg (P < 0.05) and reduced all measures of ventilation and perfusion heterogeneity (P < 0.05). By reducing flow to nondependent ventral lung regions and increasing flow to dependent dorsal lung regions, PEEP increased (P < 0.05) the dorsal-to-ventral gradient. Redistribution of blood flow with PEEP accounted for 7 +/- 3%, whereas structural factors accounted for 93 +/- 3% of the total variance in blood flow. CONCLUSIONS: The increase in dependent-to-nondependent gradient with PEEP is partially consistent with the gravitationally based lung zone model. However, the results emphasize the greater importance of anatomic factors in determining the distribution of pulmonary blood flow.

Ventilation heterogeneity is increased in hypocapnic dogs but not pigs.

Hypocapnia increases ventilation/perfusion (VA/Q) heterogeneity in dogs, possibly by adversely affecting distribution of ventilation through its effects on collateral ventilation. Because pigs lack collateral ventilation, we compared the effects of hypocapnia on ventilation heterogeneity in pentobarbital-anesthetized, mechanically-ventilated dogs and pigs. Simultaneous multiple breath washouts of helium and nitrogen were used to assess the uniformity of the ventilation distribution by the phase III (SnIII) method. Ventilation heterogeneity was partitioned into two components, e.g. convective-dependent inhomogeneity (cdi) and diffusive-convective-dependent inhomogeneity (dcdi). Pulmonary gas exchange was also measured in pigs by the multiple inert gas elimination technique. Ventilation heterogeneity was increased (P < 0.01) in hypocapnic dogs. Inspiration of CO2 decreased ventilation heterogeneity by decreasing dcdi (P < 0.01). In contrast, ventilation heterogeneity was not increased in hypocapnic pigs. However, hypocapnia increased VA/Q heterogeneity by 18% (P < 0.05) in pigs. We conclude that hypocapnia increases ventilation heterogeneity in dogs but not in pigs, most likely related to an interspecies difference in collateral ventilation.