Transient Hyperventilation Research Articles

Basic principle in the management of brain edema and elevated intracranial pressure

Background: Brain edema is a well-recognized pathophysiological secondary change after primary brain injury. The mechanism of brain edema may differ based on the types of brain edema. However, numerous ion channels are involved in its development and are therefore currently a hot target for anti-edema therapy. Here, this paper reviews the clinically important differences among the types of brain edema and a step-wise management strategy for brain edema and elevated intracranial pressure (ICP).Current Concepts: Brain edema can be classified as cytotoxic, ionic, vasogenic, and interstitial edema. Although the underlying mechanisms may differ among the various types of brain edema, multiple ion channels and the integrity of tight junctions are associated with the development of brain edema. If brain edema aggravates, the intracranial volume expands and leads to an elevation of ICP. A basic principle in the management of ICP includes proper positioning, screening for a need for extraventricular drainage, proper sedation, transient hyperventilation, assessing the intracranial water status with the serum sodium level, optimization of cerebral perfusion pressure, hyperosmolar therapy, targeted temperature management, and induction of a pharmacological coma with sedatives.Discussion and Conclusion: Stepwise treatment strategies are recommended in the management of patients with ICP crisis. Based on the principle, detailed management plans need to be adjusted based on the status of an individual patient.

Identifying Predictive Markers of CNS Oxygen Toxicity and Ketone Ester Effects on Latency to Seizure and Antioxidant Capacity

Hyperbaric oxygen (HBO2) is used in hyperbaric oxygen therapy and in undersea and aerospace medicine. What limits the use of HBO2 is the risk of seizures, i.e. central nervous system oxygen toxicity (CNS‐OT). In undersea medicine, the threat of CNS‐OT is what limits the time that the warfighter remains at depth while breathing HBO2. In addition, when breathing HBO2, various non‐convulsive signs and symptoms often precede onset of seizures, including bradycardia followed by tachycardia, hypothermia, and hyperventilation. We hypothesized that the early cardiorespiratory responses to HBO2 during the safe latent period could be used as predictive physiological markers (or physio‐markers) prior to the onset of CNS‐OT. Furthermore, using a ketone ester (KE) supplement, R,S‐1,3‐butanediol diacetoacetate ester, we posited that the KE would increase the antioxidant capacity and the latency time to seizure (LSz) when exposed to HBO2. Accordingly, 18 male, Sprague Dawley (SD) rats were implanted with DSI 4‐ET radio telemetry to record EEG, ECG, and respiratory EMG for offline analyses of physio‐markers. At least 1 week following surgery, each rat was placed in a hyperbaric chamber and “dived” to 5 ATA O2 (1 ATG/min) after oral gavage of either water (control group) or KE (treatment group). An additional 9 SD rats were also dived to 5 ATA O2, but not implanted with telemetry, to collect blood samples to measure antioxidant capacity with the RedoxSys® device before and after HBO2 exposure. HBO2 caused a 3‐phase hyperoxic ventilatory response: decreased respiration, transient hyperventilation, and a secondary later hyperventilation prior to seizures. Results showed that LSz increased in the KE group by 307% (controls: 6.42 ± 0.44 (n=15); KE: 22.16 ± 5.10 (n=18)). Additionally, minute ventilation and RR‐Interval (1/heart rate) were significantly different beginning ~15 minutes prior to onset of seizures. Receiver operating characteristic (ROC) analyses indicated that both hyperoxic hyperpnea and bradycardia were reliable physio‐markers for seizure prediction; that is, ROC for minute ventilation in both control and KE group, and for RR‐Interval in controls, was 1 (excellent predictor), and in the KE group was 0.84 (good predictor). However, core body temperature did not decrease significantly during HBO2 exposure and thus was not a physio‐marker for CNS‐OT. In addition, KE increased antioxidant capacity of blood from animals that were exposed to HBO2 with (p=0.0399) or without (p=0.0018) the development of CNS‐OT. In conclusion, hyperoxic hyperpnea and bradycardia can be used as predictive physio‐markers in conjunction with ketone therapy to reliably predict and delay CNS‐OT in rodents, and KE delays seizures in part by increasing overall antioxidant capacity during exposure to HBO2. Together this may enable safer and longer exposures for applications in undersea/aerospace medicine as well as hyperbaric oxygen therapies.

Key Brainstem Structures Activated during Hypoxic Exposure in One-day-old Mice Highlight Characteristics for Modeling Breathing Network in Premature Infants.

We mapped and characterized changes in the activity of brainstem cell groups under hypoxia in one-day-old newborn mice, an animal model in which the central nervous system at birth is particularly immature. The classical biphasic respiratory response characterized by transient hyperventilation, followed by severe ventilation decline, was associated with increased c-FOS immunoreactivity in brainstem cell groups: the nucleus of the solitary tract, ventral reticular nucleus of the medulla, retrotrapezoid/parafacial region, parapyramidal group, raphe magnus nucleus, lateral, and medial parabrachial nucleus, and dorsal subcoeruleus nucleus. In contrast, the hypoglossal nucleus displayed decreased c-FOS immunoreactivity. There were fewer or no activated catecholaminergic cells activated in the medulla oblongata, whereas ~45% of the c-FOS-positive cells in the dorsal subcoeruleus were co-labeled. Approximately 30% of the c-FOS-positive cells in the parapyramidal group were serotoninergic, whereas only a small portion were labeled for serotonin in the raphe magnus nucleus. None of the c-FOS-positive cells in the retrotrapezoid/parafacial region were co-labeled for PHOX2B. Thus, the hypoxia-activated brainstem neuronal network of one-day-old mice is characterized by (i) the activation of catecholaminergic cells of the dorsal subcoeruleus nucleus, a structure implicated in the strong depressive pontine influence previously reported in the fetus but not in newborns, (ii) the weak activation of catecholaminergic cells of the ventral reticular nucleus of the medulla, an area involved in hypoxic hyperventilation, and (iii) the absence of PHOX2B-positive cells activated in the retrotrapezoid/parafacial region. Based on these results, one-day-old mice could highlight characteristics for modeling the breathing network of premature infants.

Correlation Between Cerebral Autoregulation and Carbon Dioxide Reactivity in Patients with Traumatic Brain Injury.

Cerebral blood flow autoregulation is commonly impaired in patients with traumatic brain injury (TBI). This study was to investigate correlations between cerebral autoregulation and CO2 reactivity in patients with TBI during transient mild hypocapnia. Patients with TBI who were on mechanical ventilation were hyperventilated for approximately 60 min. Indices of autoregulation, based on a model of the relationship between arterial blood pressure and blood flow velocity (FV) (ARIabp) and, separately, between cerebral perfusion pressure and FV (ARIcpp), were calculated. Mean flow index (Mx) was also calculated. We investigated 31 consecutive patients. At baseline, median PaCO2 was 5.09 kPa (range 4.30-5.67 kPa); during hyperventilation, median PaCO2 was 4.38 kPa (range 3.72-4.96 kPa). ARI was associated with Mx (ARIabp vs. Mx: r = -0.39, p = 0.04; ARIcpp vs Mx: r = -0.67, p < 0.001). CO2 reactivity showed significant correlation with ARIcpp (r = 0.41, p = 0.04) and Mx (r = -0.37, p = 0.04). ARI after hyperventilation was significantly higher than ARI at baseline (ARIcpp: p = 0.02; ARIabp: p < 0.001). Cerebral autoregulation seemed to be well linked to CO2 reactivity during transient hyperventilation. ARIcpp had a stronger correlation with CO2 reactivity than ARIabp. ARI indicated improvement of autoregulation during hyperventilation. Cerebral autoregulation indices (ARI, Mx) were associated with each other.

Management of Intracranial Pressure.

Intracranial pressure (ICP) can be elevated in traumatic brain injury, large artery acute ischemic stroke, intracranial hemorrhage, intracranial neoplasms, and diffuse cerebral disorders such as meningitis, encephalitis, and acute hepatic failure. Raised ICP is also known as intracranial hypertension and is defined as a sustained ICP of greater than 20 mm Hg. ICP must be measured through an invasive brain catheter, typically an external ventricular catheter that can drain CSF and measure ICP, or through an intraparenchymal ICP probe. Proper recognition of the clinical signs of elevated ICP is essential for timely diagnosis and treatment to prevent cerebral hypoperfusion and possible brain death. Clinical signs of elevated ICP include headache, papilledema, nausea, and vomiting in the early phases, followed by stupor and coma, pupillary changes, hemiparesis or quadriparesis, posturing and respiratory abnormalities, and eventually cardiopulmonary arrest. Management of elevated ICP is, in part, dependent on the underlying cause. Medical options for treating elevated ICP include head of bed elevation, IV mannitol, hypertonic saline, transient hyperventilation, barbiturates, and, if ICP remains refractory, sedation, endotracheal intubation, mechanical ventilation, and neuromuscular paralysis. Surgical options include CSF drainage if hydrocephalus is present and decompression of a surgical lesion, such as an intracranial hematoma/large infarct or tumor, if the patient's condition is deemed salvageable. Future research should continue investigating medical and surgical options for the treatment of raised ICP, such as hypothermia, drugs that reduce cerebral edema, and operations aimed at reducing intracranial mass effect.

Anestesia para el tratamiento quirúrgico de aneurismas cerebrales

Although most cerebral aneurysms are asymptomatic and discovered incidentally, their rupture often results in significant morbidity and mortality. Therefore, the anesthesiologist may become involved in surgical clipping of aneurysms either electively of after subarachnoid hemorrhage. After subarachnoid hemorrhage, a multisystemic preoperative evaluation is mandatory because both neurological complications (elevated intracranial pressure, rebleeding, hydrocephalus, vasospasm) and non-neurological complications (respiratory insufficiency, cardiac dysfunction, electrolytes abnormalities, endocrine disturbances) might influence anesthetic management. Besides being prepared for potential sudden profuse bleeding, the anesthesiologist caring for craniotomy for aneurysm clipping should follow four main principles. First, acute increase in the aneurysm transmural gradient (mean arterial pressure minus intracranial pressure) should be avoided to prevent rupture or rebleeding. Second, the cerebral perfusion pressure should be maintained with euvolemia and vasopressors to avoid brain ischemia caused either by brain retractors or temporary clipping of the feeding vessel. Third, surgical exposure should be optimized by providing brain relaxation with normal cerebral oxygenation and ventilation, appropriate anesthetic choice, mannitol, and perhaps lasix, cerebrospinal fluid drainage or transient hyperventilation. Fourth, early emergence is favored to allow recognition of potentially reversible complications. By being vigilant and achieving these goals, the anesthesiologist will contribute to optimal patient outcomes.The following article provides information to guide the anesthesiologist in optimal management of surgical clipping of aneurysms.

Anesthesia for the surgical treatment of cerebral aneurysms

Although most cerebral aneurysms are asymptomatic and discovered incidentally, their rupture often results in significant morbidity and mortality. The anesthesiologist may become involved in surgical clipping of aneurysms either before aneurysm rupture or after subarachnoid hemorrhage. After subarachnoid hemorrhage, a multisystemic preoperative evaluation is mandatory because both neurological complications (elevated intracranial pressure, rebleeding, hydrocephalus, vasospasm) and non-neurological complications (respiratory insufficiency, cardiac dysfunction, electrolyte abnormalities, endocrine disturbances) might influence anesthetic management. Besides being prepared for potential sudden profuse bleeding, the anesthesiologist caring for craniotomy for aneurysm clipping should follow four main principles. First, acute increase in the aneurysm transmural gradient (mean arterial pressure minus intracranial pressure) should be avoided to prevent rupture or rebleeding. Second, the cerebral perfusion pressure should be maintained with euvolemia and vasopressors to avoid brain ischemia caused either by brain retractors or temporary clipping of the feeding vessel. Third, surgical exposure should be optimized by providing brain relaxation with normal cerebral oxygenation, normal ventilation or transient hyperventilation, appropriate anesthetic choice, mannitol and perhaps lasix, and occasionally cerebrospinal fluid drainage. Fourth, early emergence is favored to allow recognition of potentially reversible complications. By being vigilant and achieving these goals, the anesthesiologist will contribute to optimal patient outcomes. The following article provides information to guide the anesthesiologist in optimal management of surgical clipping of aneurysms.

Comment gérer l’hypertension intracrânienne réfractaire ?

Intracranial hypertension is one of the major causes of secondary injury in traumatic brain injury leading to a significant burden of morbidity and mortality. We here present a review of available therapies for the treatment of refractory intracranial hypertension that is defined as an intracranial hypertension that does not respond to the firstline therapies. Second-line therapies that are available for the treatment of refractory intracranial hypertension include mild induced hypothermia, inotropes, and vasopressors for the control of cerebral perfusion pressure, transient hyperventilation, barbiturates, and decompressive craniectomy. Apart from decompressive craniectomy, these therapies are supported by the last guidelines published by the Brain Trauma Foundation (BTF). However, the level of evidence supporting them is low to moderate. This is probably partly explained by the fact that traumatic brain injury is extremely heterogeneous and requires multimodal and individualised care, which makes randomised clinical trials difficult to set up. On-going studies like those conducted on induced hypothermia (EUROTHERM3235) and on decompressive craniectomy (RESCUEicp) may lead to new perspectives for the management of patients suffering from refractory intracranial hypertension.

The kreisler mutation leads to the loss of intrinsically hypoxia-activated spots in the region of the retrotrapezoid nucleus/parafacial respiratory group

Acute hypoxia elicits a biphasic respiratory response characterized in the newborn by a transient hyperventilation followed by a severe decrease in respiratory drive known as hypoxic respiratory depression. Medullary O(2) chemosensitivity is known to contribute to respiratory depression induced by hypoxia, although precise involvement of cell populations remains to be determined. Having a thorough knowledge of these populations is of relevance because perturbations in the respiratory response to hypoxia may participate in respiratory diseases in newborns. We aimed to analyze the hypoxic response of ponto-medullary cell populations of kreisler mutant mice. These mice have defects in a gene expressed in two rhombomeres encompassing a part of the medulla oblongata implicated in hypoxic respiratory depression. Central responses to hypoxia were analyzed in newborn mice by measuring respiratory rhythm in ex vivo caudal pons-medullary-spinal cord preparations and c-fos expression in wild-type and kreisler mutants. The homozygous kreisler mutation, which eliminates most of rhombomere 5 and mis-specifies rhombomere 6, abolished (1) an early decrease in respiratory frequency within 10 min of hypoxia and (2) an intrinsic hypoxic activation, which is characterized by an increase in c-fos expression in the region of the ventral medullary surface encompassing the retrotrapezoid nucleus/parafacial respiratory group expressing Phox2b. This increase in c-fos expression persisted in wild-type Phox2b-negative and Phox2b-positive cells after blockade of synaptic transmission and rhythmogenesis by a low [Ca(2+)](0). Another central response was retained in homozygous kreisler mutant mice; it was distinguished by (1) a delayed (10-30 min) depression of respiratory frequency and (2) a downregulation of c-fos expression in the ventrolateral reticular nucleus of the medulla, the nucleus of the solitary tract, and the area of the A5 region. Thus, two types of ponto-medullary cell groups, with distinct anatomical locations, participate in central hypoxic respiratory depression in newborns.

Stabilizing Ventilation in OSAHS with CPAP Emergent Periodic Breathing Through the Use of Dead Space

Stabilizing Ventilation in OSAHS with CPAP Emergent Periodic Breathing Through the Use of Dead Space

Mapping Transient Hyperventilation Induced Alterations with Estimates of the Multi-Scale Dynamics of BOLD Signal.

Temporal blood oxygen level dependent (BOLD) contrast signals in functional MRI during rest may be characterized by power spectral distribution (PSD) trends of the form 1/fα. Trends with 1/f characteristics comprise fractal properties with repeating oscillation patterns in multiple time scales. Estimates of the fractal properties enable the quantification of phenomena that may otherwise be difficult to measure, such as transient, non-linear changes. In this study it was hypothesized that the fractal metrics of 1/f BOLD signal trends can map changes related to dynamic, multi-scale alterations in cerebral blood flow (CBF) after a transient hyperventilation challenge. Twenty-three normal adults were imaged in a resting-state before and after hyperventilation. Different variables (1/f trend constant α, fractal dimension Df, and, Hurst exponent H) characterizing the trends were measured from BOLD signals. The results show that fractal metrics of the BOLD signal follow the fractional Gaussian noise model, even during the dynamic CBF change that follows hyperventilation. The most dominant effect on the fractal metrics was detected in grey matter, in line with previous hyperventilation vaso-reactivity studies. The α was able to differentiate also blood vessels from grey matter changes. Df was most sensitive to grey matter. H correlated with default mode network areas before hyperventilation but this pattern vanished after hyperventilation due to a global increase in H. In the future, resting-state fMRI combined with fractal metrics of the BOLD signal may be used for analyzing multi-scale alterations of cerebral blood flow.

Mechanisms of the cerebrovascular response to apnoea in humans

We measured ventilation, arterial O2 saturation, end‐tidal CO2 (PET,CO2), blood pressure (intra‐arterial catheter or photoelectric plethysmograph), and flow velocity in the middle cerebral artery (CFV) (pulsed Doppler ultrasound) in 17 healthy awake subjects while they performed 20 s breath holds under control conditions and during ganglionic blockade (intravenous trimethaphan, 4.4 ± 1.1 mg min−1 (mean ±s.d.)). Under control conditions, breath holding caused increases in PET,CO2 (7 ± 1 mmHg) and in mean arterial pressure (MAP) (15 ± 2 mmHg). A transient hyperventilation (PET,CO2−7 ± 1 mmHg vs. baseline) occurred post‐apnoea. CFV increased during apnoeas (by 42 ± 3 %) and decreased below baseline (by 20 ± 2 %) during post‐apnoea hyperventilation. In the post‐apnoea recovery period, CFV returned to baseline in 45 ± 4 s. The post‐apnoea decrease in CFV did not occur when hyperventilation was prevented. During ganglionic blockade, which abolished the increase in MAP, apnoea‐induced increases in CFV were partially attenuated (by 26 ± 2 %). Increases in PET,CO2 and decreases in oxyhaemoglobin saturation (Sa,O2) (by 2 ± 1 %) during breath holds were identical in the intact and blocked conditions. Ganglionic blockade had no effect on the slope of the CFV response to hypocapnia but it reduced the CFV response to hypercapnia (by 17 ± 5 %). We attribute this effect to abolition of the hypercapnia‐induced increase in MAP. Peak increases in CFV during 20 s Mueller manoeuvres (40 ± 3 %) were the same as control breath holds, despite a 15 mmHg initial, transient decrease in MAP. Hyperoxia also had no effect on the apnoea‐induced increase in CFV (40 ± 4 %). We conclude that apnoea‐induced fluctuations in CFV were caused primarily by increases and decreases in arterial partial pressure of CO2 (Pa,CO2) and that sympathetic nervous system activity was not required for either the initiation or the maintenance of the cerebrovascular response to hyper‐ and hypocapnia. Increased MAP or other unknown influences of autonomic activation on the cerebral circulation played a smaller but significant role in the apnoea‐induced increase in CFV; however, negative intrathoracic pressure and the small amount of oxyhaemoglobin desaturation caused by 20 s apnoea did not affect CFV.

Efficacy of hyperventilation, blood pressure elevation, and metabolic suppression therapy in controlling intracranial pressure after head injury.

Hyperventilation therapy, blood pressure augmentation, and metabolic suppression therapy are often used to reduce intracranial pressure (ICP) and improve cerebral perfusion pressure (CPP) in intubated head-injured patients. In this study, as part of routine vasoreactivity testing, these three therapies were assessed in their effectiveness in reducing ICP. Thirty-three patients with a mean age of 33 +/- 13 years and a median Glasgow Coma Scale (GCS) score of 7 underwent a total of 70 vasoreactivity testing sessions from postinjury Days 0 to 13. After an initial 133Xe cerebral blood flow (CBF) assessment, transcranial Doppler ultrasonography recordings of the middle cerebral arteries were obtained to assess blood flow velocity changes resulting from transient hyperventilation (57 studies in 27 patients), phenylephrine-induced hypertension (55 studies in 26 patients), and propofol-induced metabolic suppression (43 studies in 21 patients). Changes in ICP, mean arterial blood pressure (MABP), CPP, PaCO2, and jugular venous oxygen saturation (SjvO2) were recorded. With hyperventilation therapy, patients experienced a mean decrease in PaCO2 from 35 +/- 5 to 27 +/- 5 mm Hg and in ICP from 20 +/- 11 to 13 +/- 8 mm Hg (p < 0.001). In no patient who underwent hyperventilation therapy did SjvO2 fall below 55%. With induced hypertension, MABP in patients increased by 14 +/- 5 mm Hg and ICP increased from 16 +/- 9 to 19 +/- 9 mm Hg (p = 0.001). With the aid of metabolic suppression, MABP remained stable and ICP decreased from 20 +/- 10 to 16 +/- 11 mm Hg (p < 0.001). A decrease in ICP of more than 20% below the baseline value was observed in 77.2, 5.5, and 48.8% of hyperventilation, induced-hypertension, and metabolic suppression tests, respectively (p < 0.001 for all comparisons). Predictors of an effective reduction in ICP included a high PaCO2 for hyperventilation, a high study GCS score for induced hypertension, and a high PaCO2 and a high CBF for metabolic suppression. Of the three modalities tested to reduce ICP, hyperventilation therapy was the most consistently effective, metabolic suppression therapy was variably effective, and induced hypertension was generally ineffective and in some instances significantly raised ICP. The results of this study suggest that hyperventilation may be used more aggressively to control ICP in head-injured patients, provided it is performed in conjunction with monitoring of SjvO2.

The effects of endothelin-1 on the cardiorespiratory physiology of the freshwater trout (Oncorhynchus mykiss) and the marine dogfish (Squalus acanthias).

The aim of the present study was to evaluate the effects of endothelin-l-elicited cardiovascular events on respiratory gas transfer in the freshwater rainbow trout (Oncorhynchus mykiss) and the marine dogfish (Squalus acanthias). In both species, endothelin-1 (666 pmol kg(-1)) caused a rapid (within 4 min) reduction (ca. 30-50 mmHg) in arterial blood partial pressure of O2. The effects of endothelin-1 on arterial blood partial pressure of CO2 were not synchronised with the changes in O2 partial pressure and the responses were markedly different in trout and dogfish. In trout, arterial CO2 partial pressure was increased transiently by approximately 1.0 mmHg but the onset of the response was delayed and occurred 12 min after endothelin-1 injection. In contrast, CO2 partial pressure remained more-or-less constant in dogfish after injection of endothelin-1 and was increased only slightly (approximately 0.1 mmHg) after 60 min. Pre-treatment of trout with bovine carbonic anhydrase (5 mg ml(-1)) eliminated the increase in CO2 partial pressure that was normally observed after endothelin-1 injection. In both species, endothelin-1 injection caused a decrease in arterial blood pH that mirrored the changes in CO2 partial pressure. Endothelin-1 injection was associated with transient (trout) or persistent (dogfish) hyperventilation as indicated by pronounced increases in breathing frequency and amplitude. In trout, arterial blood pressure remained constant or was decreased slightly and was accompanied by a transient increase in systemic resistance, and a temporary reduction in cardiac output. The decrease in cardiac output was caused solely by a reduction in cardiac frequency; cardiac stroke volume was unaffected. In dogfish, arterial blood pressure was lowered by approximately 10 mmHg at 6-10 min after endothelin-1 injection but then was rapidly restored to pre-injection levels. The decrease in arterial blood pressure reflected an increase in branchial vascular resistance (as determined using in situ perfused gill preparations) that was accompanied by simultaneous decreases in systemic resistance and cardiac output. Cardiac frequency and stroke volume were reduced by endothelin-1 injection and thus both variables contributed to the changes in cardiac output. We conclude that the net consequences of endothelin-1 on arterial blood gases result from the opposing effects of reduced gill functional surface area (caused by vasoconstriction) and an increase in blood residence time within the gill (caused by decreased cardiac output.

Carbon dioxide reactivity, pressure autoregulation, and metabolic suppression reactivity after head injury: a transcranial Doppler study.

Contemporary management of head-injured patients is based on assumptions about CO2 reactivity, pressure autoregulation (PA), and vascular reactivity to pharmacological metabolic suppression. In this study, serial assessments of vasoreactivity of the middle cerebral artery (MCA) were performed using bilateral transcranial Doppler (TCD) ultrasonography. Twenty-eight patients (mean age 33 +/- 13 years, median Glasgow Coma Scale score of 7) underwent a total of 61 testing sessions during postinjury Days 0 to 13. The CO2 reactivity (58 studies in 28 patients), PA (51 studies in 23 patients), and metabolic suppression reactivity (35 studies in 16 patients) were quantified for each cerebral hemisphere by measuring changes in MCA velocity in response to transient hyperventilation, arterial blood pressure elevation, or propofol-induced burst suppression, respectively. One or both hemispheres registered below normal vasoreactivity scores in 40%, 69%, and 97% of study sessions for CO2 reactivity, PA, and metabolic suppression reactivity (p < 0.0001), respectively. Intracranial hypertension, classified as intracranial pressure (ICP) greater than 20 mm Hg at the time of testing, was associated with global impairment of CO2 reactivity, PA, and metabolic suppression reactivity (p < 0.05). A low baseline cerebral perfusion pressure (CPP) was also predictive of impaired CO2 reactivity and PA (p < 0.01). Early postinjury hypotension or hypoxia was also associated with impaired CO2 reactivity (p < 0.05), and hemorrhagic brain lesions in or overlying the MCA territory were predictive of impaired metabolic suppression reactivity (p < 0.01). The 6-month Glasgow Outcome Scale score correlated with the overall degree of impaired vasoreactivity (p < 0.05). During the first 2 weeks after moderate or severe head injury, CO2 reactivity remains relatively intact, PA is variably impaired, and metabolic suppression reactivity remains severely impaired. Elevated ICP appears to affect all three components of vasoreactivity that were tested, whereas other clinical factors such as CPP, hypotensive and hypoxic insults, and hemorrhagic brain lesions have distinctly different impacts on the state of vasoreactivity. Incorporation of TCD ultrasonography-derived vasoreactivity data may facilitate more injury- and time-specific therapies for head-injured patients.

Neural drives and breathing stability.

Cessation of breathing and cyclic variations in tidal volume and frequency are far more likely to be precipitated when hypoxia or transient hyperventilation produces subnormal levels of PCO2 in NREM sleep and at sleep onset, than in awake subjects. The ability of the awake subject to breathe with only rare apneas and oscillations in ventilation at levels of PCO2 considerably below resting seems to depend on the interplay of chemical and neural drives.

Effect of transient moderate hyperventilation on dynamic cerebral autoregulation after severe head injury.

This study was undertaken to evaluate the effect of acute moderate hyperventilation on cerebral autoregulation in head-injured patients. Dynamic cerebral autoregulation was analyzed by use of transcranial doppler ultrasonography before and after hyperventilation in 10 patients with severe head injury. All of the patients were artificially ventilated and underwent continuous monitoring of arterial blood pressure, intracranial pressure, and end-tidal carbon dioxide. To test autoregulation, rapid transient decreases in systemic blood pressure were achieved by quickly releasing large blood pressure cuffs that were inflated around both thighs. This resulted in a drop of 24 +/- 6 mm Hg in mean systemic blood pressure, which lasted an average of 49 +/- 24 seconds. Cerebral blood flow velocity was monitored continuously in both middle cerebral arteries by use of transcranial doppler ultrasonography. The percentage change in middle cerebral artery velocity was used as an index of the change in cerebral blood flow during the autoregulatory response. The change in estimated cerebrovascular resistance, immediately after the blood pressure drop, or the rate of regulation was used to analyze the effectiveness of the cerebral autoregulation. This value was calculated by determining the rate of increase in middle cerebral artery velocity during the 1st 5 seconds after a blood pressure drop, relative to the rate of increase of the cerebral perfusion pressure. The average rate of regulation during normocapnia at pCO2 of 37 mm Hg was 11.4 +/- 5% per second. After reduction of the pCO2 to 28 mm Hg, the average rate of regulation improved significantly (P < 0.001) to 17.7 +/- 6% per second. Autoregulation improved, despite no significant change in the cerebral perfusion pressure during hyperventilation. The degree of improvement in autoregulation was significantly correlated with the CO2 reactivity (r = 0.45, P < 0.05) but did not correlate (r = -0.23, P = 0.33) with the change in arterial pH value after hyperventilation. These results confirm the finding that dynamic autoregulation is disturbed in severe head injury and that moderate transient hyperventilation can temporarily improve the efficiency of the autoregulatory response, probably as a result of a transient increase in vascular tone.

Effects of REM Sleep on the Ventilatory Response to Airway Occlusion in the Dog

We determined the effects of sleep state on the ventilatory response following transient airway occlusion and on the response to vagal blockade in the unanesthetized sleeping dog. Three tracheotomized dogs underwent repeated occlusions (159 trials) during rapid eye movement (REM) and nonrapid eye movement (NREM) sleep. In all sleep states we found significant but variable transient hyperventilation following release of occlusion. In NREM sleep, a significant central apnea [expiratory time (TE) prolonged 2-10 times control] followed the hyperpneic response, so long as the increase in tidal volume (VT) during the hyperpnea exceeded three times control VT, that is, a volume-dependent apneic threshold. In REM sleep with maintained levels of eye movement density, hyperventilation commonly followed release of obstruction but only very rarely did VT exceed the volume threshold, and central apnea was rare. Cervical vagal blockade was used to show that significant inhibitory pulmonary stretch receptor reflexes were present in both NREM and REM sleep, although the strength of the reflex was diminished in REM. We postulate that the phasic events of REM sleep inhibit the increase in VT in response to the chemical stimuli accumulated during airway occlusion and also interfere with the prolongation of TE in response to lung stretch and/or transient hypocapnia. The result is that central apnea occurs only very rarely in REM sleep.

A volume-dependent apneic threshold during NREM sleep in the dog.

We determined the causes of central apnea that commonly follow the hyperpnea resulting from brief airway occlusion during non-rapid-eye-movement (NREM) sleep. Ventilation and end-tidal gases were measured before, during, and after 214 trials of 15-20 s of tracheal occlusion in three dogs during NREM sleep. Airway occlusion was accompanied by progressive increases in inspiratory effort and was followed by transient one- to four-breath hyperapneas, with subsequent central apnea [3-15 times eupneic control expiratory duration (TE)] in 62% of occlusion trials. Significant TE prolongation after hyperventilation did not occur until tidal volume (VT) was three times greater than control; i.e., there was a volume-dependent apneic threshold. Transient electroencephalogram arousal at the end of the occlusion often augmented VT, thereby contributing to the subsequent central apnea; however, arousal was not required for the apnea to occur. Significant transient hypocapnia (up to -12 Torr arterial PCO2) commonly occurred after release of airway occlusion but was not closely correlated with the length of central apnea. During vagal blockade, after release of airway occlusion, significant transient hyperventilation occurred but at VT < 40% greater than control, and TE prolongation was markedly reduced. In summary, after release of airway occlusion in NREM sleep, 1) VT greater than three times eupnea was necessary to cause central apnea, 2) transient arousal at the termination of airway occlusion caused longer apneas by augmenting VT, and 3) transient hypocapnia per se made a significant but minor contribution to the postocclusion central apnea.

Respiratory and circulatory activities in carotid body-resected humans.

The respiratory and circulatory activities of patients who underwent carotid body resection (CBR) more than two decades ago were reviewed. No significant ventilatory response to continuous hypoxia was observed. However, in response to stimulation of peripheral chemoreceptors, transient hyperventilation occurred before hypoxemic blood arrived at the central nervous system (single-breath test), which indicated the presence of weak peripheral chemosensitivity. Because of this slight residual peripheral chemosensitivity, which was found shortly after the operation and apparently remained more or less unchanged for greater than 20 years, peripheral chemoreceptor activity, which has been reported in other animal species, does not seem to have returned. Delayed hypoxic hyperventilation reported in dogs and cats with CBR was not observed. Hypoxia significantly depressed the ventilatory response to CO2, but the delayed ventilatory depression with time that has been demonstrated in normal subjects did not occur. In our circulatory studies, hypoxia augmented the heart rate and slightly depressed the stroke volume and total peripheral resistance in the systemic circulation but induced no appreciable changes in arterial blood pressure or cardiac output. We used these results to partition the relative contributions to the overall circulatory response of carotid body stimulation, pulmonary inflation, and other modifying influences. From these calculations, it was inferred that the carotid body reflex plays a dominant role in vascular activities whereas the pulmonary inflation reflex dominates in cardiac activities in humans.