Do we feel pain during anesthesia? A critical review on surgery-evoked circulatory changes and pain perception.

The difficulty of defining the three so-called components of « an-esthesia ¼ is emphasized: hypnosis, absence of movement, and adequacy of anti-nociception (intraoperative « analgesia ¼). Data obtained from anesthetized animals or humans delineate the activation of cardiac and vasomotor sympathetic reflex (somato-sympathetic reflex) and the cardiac parasympathetic deactivation observed following somatic stimuli. Sympathetic activation and parasympathetic deactivation are used as monitors to address the adequacy of intraoperative anti-nociception. Finally, intraoperative nociception through the administration of nonopioid analgesics vs. opioid analgesics is considered to achieve minimal postoperative side effects.

Swift recovery of severe hypoxemic pneumonia upon morbid obesity.

A morbidly obese (body mass index = 55.5) female patient presented with severe hypoxemic community acquired pneumonia [PaO2/FiO2 (P/F) = 57] with primarily right basal atelectasis, but without bilateral opacities in the upper lobes on the chest X-ray. Major O2 desaturations led the nurses to object to moving the patient to the prone position: muscle relaxation combined to prone position was impossible. Therefore, stringent 60 degrees reverse Trendelenburg legs down position was constantly maintained during mechanical ventilation through the endotracheal tube, using low pressure support (pressure support = 5-10 cmH2O) and high positive end-expiratory pressure (PEEP). PEEP was progressively increased to 20 cmH2O, and little or no sedation was used. A P/F improvement from 57 to 200 over three days allowed removing the tracheal tube. The patient was discharged 13 days after admission. In this paper, the use of high PEEP in the context of morbid obesity, and low pressure support are discussed.

Clonidine and dexmedetomidine increase the pressor response to norepinephrine in experimental sepsis: a pilot study.

OBJECTIVE: During septic shock, vasopressors are a cornerstone of therapy. In septic shock, very high doses of vasopressors sometimes have to be used due to vascular desensitization, the mechanisms of which are poorly understood. This study assesses whether α-2 agonists increase pressor responsiveness following lipopolysaccharide administration. DESIGN: Parallel groups of animals (n = 7 per group) subjected to pharmacologic interventions. SETTING: Physiology laboratory. SUBJECTS: Rats. INTERVENTIONS: In anesthetized rats, the pressor responses to increasing doses of norepinephrine (norepinephrine-systolic pressure curve) were assessed during a baseline period, after injection of saline or lipopolysaccharide, and after subsequent injection of saline, dexmedetomidine (100 µg/kg IV), or clonidine (200 µg/kg IV). MEASUREMENTS AND MAIN RESULTS: Differences in the slopes of the norepinephrine-pressure curves were assessed across drug treatments and intervals. The pressor dose of norepinephrine necessary to increase systolic pressure by 33 and 100 mm Hg (pressor dose 33 and pressor dose 100) was determined. Pressor responsiveness to norepinephrine decreased slightly over time in the saline-saline group (saline 1 or 2 vs baseline: mean decrease of the slope, 2 mm Hg/µg/kg norepinephrine; p < 0.05), whereas there was a large decrease after lipopolysaccharide (lipopolysaccharide vs baseline: mean decrease of the slope, 7.2; p < 0.001). Clonidine alone had no effect, but when administered following lipopolysaccharide, it caused a striking increase in pressor responsiveness (mean slope after lipopolysaccharide, 10.7 [95% CI, 9.9-11.6]; after clonidine, 17.5 [95% CI, 16.7-18.4]). Similarly, dexmedetomidine administered after lipopolysaccharide caused a large increase in pressor responsiveness above lipopolysaccharide values. Accordingly the pressor dose 33 and pressor dose 100 values were lowered following lipopolysaccharide and restored by α-2 agonists. CONCLUSIONS: The pressor response to norepinephrine was reduced following lipopolysaccharide and increased to baseline levels following α-2 agonists.

K-nearest-neighbor conditional entropy approach for the assessment of the short-term complexity of cardiovascular control.

Complexity analysis of short-term cardiovascular control is traditionally performed using entropy-based approaches including corrective terms or strategies to cope with the loss of reliability of conditional distributions with pattern length. This study proposes a new approach aiming at the estimation of conditional entropy (CE) from short data segments (about 250 samples) based on the k-nearest-neighbor technique. The main advantages are: (i) the control of the loss of reliability of the conditional distributions with the pattern length without introducing a priori information; (ii) the assessment of complexity indexes without fixing the pattern length to an arbitrary low value. The approach, referred to as k-nearest-neighbor conditional entropy (KNNCE), was contrasted with corrected approximate entropy (CApEn), sample entropy (SampEn) and corrected CE (CCE), being the most frequently exploited approaches for entropy-based complexity analysis of short cardiovascular series. Complexity indexes were evaluated during the selective pharmacological blockade of the vagal and/or sympathetic branches of the autonomic nervous system. We found that KNNCE was more powerful than CCE in detecting the decrease of complexity of heart period variability imposed by double autonomic blockade. In addition, KNNCE provides indexes indistinguishable from those derived from CApEn and SampEn. Since this result was obtained without using strategies to correct the CE estimate and without fixing the embedding dimension to an arbitrary low value, KNNCE is potentially more valuable than CCE, CApEn and SampEn when the number of past samples most useful to reduce the uncertainty of future behaviors is high and/or variable among conditions and/or groups.

Short-term complexity indexes of heart period and systolic arterial pressure variabilities provide complementary information.

It is unclear whether the complexity of the variability of the systolic arterial pressure (SAP) provides complementary information to that of the heart period (HP). The complexity of HP and SAP variabilities was assessed from short beat-to-beat recordings (i.e., 256 cardiac beats). The evaluation was made during a pharmacological protocol that induced vagal blockade with atropine or a sympathetic blockade (beta-adrenergic blockade with propranolol or central sympathetic blockade with clonidine) alone or in combination, during a graded head-up tilt, and in patients with Parkinson's disease (PD) without orthostatic hypotension undergoing orthostatic challenge. Complexity was quantified according to the mean square prediction error (MSPE) derived from univariate autoregressive (AR) and multivariate AR (MAR) models. We found that: 1) MSPE(MAR) did not provide additional information to that of MSPE(AR); 2) SAP variability was less complex than that of HP; 3) because HP complexity was reduced by either vagal blockade or vagal withdrawal induced by head-up tilt and was unaffected by beta-adrenergic blockade, HP was under vagal control; 4) because SAP complexity was increased by central sympathetic blockade and was unmodified by either vagal blockade or vagal withdrawal induced by head-up tilt, SAP was under sympathetic control; 5) SAP complexity was increased in patients with PD; and 6) during orthostatic challenge, the complexity of both HP and SAP variabilities in patients with PD remained high, thus indicating both vagal and sympathetic impairments. Complexity indexes derived from short HP and SAP beat-to-beat series provide complementary information and are helpful in detecting early autonomic dysfunction in patients with PD well before circulatory symptoms become noticeable.

A beat-by-beat, on-line, cardiovascular index, CARDEAN, to assess circulatory responses to surgery: a randomized clinical trial during spine surgery.

Automated assessment of circulatory response to surgical stimuli is unsolved. Would detection of cardiac baroreflex inhibition assess adequacy of intra-operative anti-nociception upon incision, as performed on-line on a beat-by-beat basis by a cardiovascular index, CARDEAN™? 18 ASA I-II patients undergoing spinal disc repair were studied, in a prospective randomized single-blinded trial (observational study). During infusion of propofol to maintain bispectral index between 40 and 60, patients were allocated to receive an effect site target-controlled infusion of remifentanil at Ce = 2 or 4 ng ml(-1). Upon incision and during surgery, circulatory response was assessed using beat-by-beat measurements of minor hypertension and tachycardia to give a cardiovascular index, CARDEAN, scaled between 0 and 100. Upon skin incision, CARDEAN increased in the remifentanil Ce = 2 ng ml(-1) group (n = 7, P < 0.05), while it did not increase in the remifentanil Ce = 4 ng ml(-1) group (n = 7, P = 0.18). During surgery, retrospectively, CARDEAN > 60 was associated with tachycardia and hypertension (P (k) = 0.81 ± 0.10). Changes in CARDEAN appeared linked to adequacy of anti-nociception.

Isoflurane suppresses central cardiac parasympathetic activity in rats: a pilot study.

BACKGROUND: Intraoperative circulatory stability is a function of both cardiac parasympathetic activity and cardiac and vascular sympathetic activity; however, cardiac parasympathetic activity is rarely considered. This experiment addresses the effect of isoflurane on central cardiac parasympathetic control, i.e., cardiac vagal motoneurons (CVM), which are located in the nucleus ambiguous of the brain stem and project to the sinus node. METHODS: In urethane-anesthetized rats, the single unit activity of CVM, antidromically identified from the craniovagal cardiac branch, was observed following the introduction of isoflurane. Isoflurane was introduced slowly over 10 minutes to achieve 2% end tidal CO2 (ETCO2) RESULTS: Following the introduction of isoflurane (2% ETCO2), all CVM were almost entirely silenced (N=6 cells in 6 different rats, 1.9 ±2.4 vs. 0.2 ±0.3 Hz, P<0.05). CONCLUSION: The data obtained with antidromically identified cardiac vagal motoneurons confirm data obtained previously with whole vagal nerve recordings. The authors speculate on how the blunting of the cardiac parasympathetic activity by isoflurane that was observed in rats may impact intraoperative circulatory stability in humans.

Recruitment of cardiac parasympathetic activity: effects of clonidine on cardiac vagal motoneurones, pressure lability, and cardiac baroreflex slope in rats.

BACKGROUND: Association of low cardiac vagal activity and poor outcome is demonstrated in the cardiology setting. This has not been addressed in the postoperative setting. Cardiac vagal motoneurones (CVMs) in the brain stem generate sinus arrhythmia. They may reduce blood pressure (BP) variability ('pressure lability'). An alpha-2 agonist, clonidine, was administered to assess whether cardiac vagal activity could be recruited from a very low baseline activity, increase the sensitivity of the cardiac baroreflex and sinus arrhythmia, and reduce the pressure lability. METHODS: In ventilated anaesthetized rats, single-unit activity from antidromically identified CVMs was recorded. Given complex interactions within the cardiac ganglion, a peripherally acting beta-blocker, atenolol, was administered before clonidine. RESULTS: Atenolol 2 mg kg(-1) i.v. did not change systolic BP (SBP), CVM firing rate and slope of the cardiac baroreflex analysed at CVM (SBP-CVM unit activity relationship) level, or at the heart level (SBP-RR interval relationship) but evoked a significant bradycardia. In the presence of atenolol 2 mg kg(-1) h(-1), clonidine 10-100 microg kg(-1) i.v. evoked a significant reduction in SBP, a large increase of CVM firing rate from a very low base line [0.16 (sd 0.28) to 1.37 (1.21) spikes s(-1), n=7 cells], and increased the slope of the cardiac baroreflex analysed at the CVM level or at the heart level. sds of SBP were reduced, and that of RR interval was increased. CONCLUSIONS: Following peripheral beta-blockade, clonidine activated CVMs from a very low baseline, increased the slope of the cardiac baroreflex and sinus arrhythmia, and reduced pressure lability.

Post-operative pressure lability and cardiac baroreflex in normotensive patients as a function of age.

BACKGROUND: Pressure lability may be linked to the loss of the cardiac baroreflex. The reduction of the sensitivity of the cardiac baroreflex has not been delineated in the post-operative period according to age in normotensive patients. This study addresses pressure lability and slope of the cardiac baroreflex as a function of age. METHODS: Patients were allocated to the following three groups: young (20-39 years, n=7), middle aged (40-59 years, n=7) and elderly (60-79 years, n=6), and studied before minor intra-abdominal surgery under CO(2) peritoneal insufflation and nitrous oxide-isoflurane-sufentanil anesthesia, up to 24 h after extubation. An electrocardiogram and non-invasive beat-by-beat pressure monitoring (Finapres) allowed offline calculation of the sensitivity of the cardiac baroreflex ('sequence' technique) and standard deviation (SD) of heart rate (HR; HR variability) and systolic blood pressure (SBP; pressure lability). RESULTS: Before anesthesia, (a) an inverse relationship was observed between the slope of the cardiac baroreflex and age and (b) a trend (P<0.09) existed between the slope of the cardiac baroreflex and pressure lability, irrespective of age. During the early post-operative period, young patients returned to their baseline slope of the cardiac baroreflex; no inverse relationship between increased SD of SBP and decreased SD of RR interval was observed. Middle-aged and elderly patients displayed a depressed slope of the cardiac baroreflex both before and after anesthesia. CONCLUSION: At variance with the pre-operative period, no simple inverse relationship was observed between increased pressure lability and depressed HR variability in young patients during the early post-operative period.

Unusual sinus arrhythmia.

A juxtaposition of long and short RR intervals was observed in 2 hypertensive patients recovering from major surgery under spontaneous ventilation. Sinus rhythm was ascertained throughout the recording. These oscillations could not be linked one-to-one to ventilatory cycles.

Reduced blood pressure lability during emergence from anaesthesia in rats: a pilot study using clonidine.

BACKGROUND: In the post-operative setting, pressure lability is increased in hypertensive patients. alpha-2 agonists were shown qualitatively to reduce this lability qualitatively. Here, upon immobilization combined with emergence from anesthesia in rats and clonidine administration, pressure lability was quantitatively assessed and related to baroreflex sensitivity. METHODS: After local anesthesia of all incisions and surgical wounds and myorelaxation with metocurine, rats had halothane withdrawn for 60 min. Rats received (a) saline (n=8), (b) clonidine 30 microg/kg i.v (n=8) simultaneous to halothane discontinuation and (c) halothane readministration (n=8) 20 min after halothane discontinuation. Pressure lability was quantitatively assessed using occurrence/amplitude of peaks in systolic blood pressure (SBP) and cardiac baroreflex slope. RESULTS: Clonidine was associated with partial blunting of hypertension, reduced standard deviation of SBP, reduced number and amplitude of peaks in systolic pressure. Clonidine was also associated with increased slope of the cardiac baroreflex upon early intervals of emergence, but not at later intervals. CONCLUSION: Clonidine reduces pressure lability upon immobilization stress combined to emergence from anesthesia, via parasympathetic activation and possibly sympathetic inhibition during early emergence as opposed to sympathetic inhibition during late emergence.

Effect of systemic B-type natriuretic peptide on cardiac vagal motoneuron activity.

Intravenous B-type natriuretic peptide (BNP) enhances the bradycardia of reflexes from the heart, including the von Bezold-Jarisch reflex, but its site of action is unknown. The peptide is unlikely to penetrate the blood-brain barrier but could act on afferent or efferent reflex pathways. To investigate the latter, two types of experiment were performed on urethane-anesthetized (1.4 g/kg iv) rats. First, the activity was recorded extracellularly from single cardiac vagal motoneurons (CVMs) in the nucleus ambiguus. CVMs were identified by antidromic activation from the cardiac vagal branch and by their barosensitivity. Phenyl biguanide (PBG), injected via the right atrium in bolus doses of 1-5 mug to evoke the von Bezold-Jarisch reflex, caused a dose-related increase in CVM activity and bradycardia. BNP infusion (25 pmol.kg(-1).min(-1) iv) significantly enhanced both the CVM response to PBG (n = 5 rats) and the reflex bradycardia, but the log-linear relation between those two responses over a range of PBG doses was unchanged by BNP. The reflex bradycardia was not enhanced in five matched time-control rats receiving only vehicle infusions. In five other rats the cervical vagi were cut and the peripheral right vagus was stimulated supramaximally at frequencies of 1-20 Hz. The bradycardic responses to these stimuli were unchanged before, during, and after BNP infusion. We conclude that systemic BNP in a moderate dose enhances the von Bezold-Jarisch reflex activation of CVM, in parallel with the enhanced reflex bradycardia. That enhancement is due entirely to an action before the vagal efferent arm of the reflex pathway.

Beat-by-beat cardiovascular index to predict unexpected intraoperative movement in anesthetized unparalyzed patients: a retrospective analysis.

OBJECTIVE: Unexpected intraoperative movement may be detrimental during delicate surgery. This study tested retrospectively an algorithm based on beat-by-beat circulatory variables (incorporated into a Cardiovascular depth of anesthesia index: CARDEAN in relationship to unexpected movement, and compared its performance to that of the electroencephalogram (EEG)-derived index: BIS-XP 4.0. METHODS: 40 ASA I or II patients presenting for knee surgery had EEG (BIS XP 4.0), beat-by-beat (Finapres) finger non-invasive blood pressure (BP), conventional brachial BP and electrocardiogram (EKG) monitors attached. Anesthesia was induced and maintained with propofol and remifentanil. Before incision, the propofol concentration was set to maintain BIS < 60. From incision to emergence, the anesthesiologist was denied access to BIS or Finapres. Anesthesia adjustment was titrated at the discretion of the anesthesiologist according to conventional signs only: brachial BP, EKG, eyelash reflex, movement. Occurrences of movement and eye signs (divergence of eyeballs, tears, corneal reflex, eyelash reflex) were observed. The CARDEAN algorithm was written retrospectively and tested vs. BIS. RESULTS: 11 movements occurred in 8 patients. CARDEAN > 60 predicted movement in 30% of the cases, 15 to 274 s before movement (sensitivity: 100%, specificity: 95%; relative operating curve ROC = 0.98; prediction probability pk = 0.98). BIS > 60 predicted movement in 19% of cases (sensitivity: 64%; specificity: 94%, ROC: 0.85, pk: 0.85). CONCLUSION: Retrospectively, a cardiovascular index predicted unexpected intraoperative movements. Prospective validation is needed.

Spontaneous baroreflex cardiac sensitivity in end-stage liver disease: effect of liver transplantation.

BACKGROUND AND OBJECTIVE: End-stage liver disease is associated with an imbalance in the autonomic nervous system. The purpose of this study was to estimate the effect of liver transplantation on this imbalance. METHOD: The study involved 10 patients undergoing liver transplantation and 9 patients without liver impairment undergoing liver surgery. The spontaneous baroreflex sensitivity was measured before and 1 month after surgery for the liver surgery group; before and 1, 3, 6, 12 and 18 months after orthotopic liver transplantation. RESULTS: The spontaneous baroreflex slope of patients with end-stage liver disease was decreased before liver transplantation compared to the liver surgery group (3.9 +/- 2.5 ms mmHg(-1) vs. 9.9 +/- 5.0 ms mmHg(-1), P = 0.002). The mean slope was significantly increased at 12 and 18 months compared to the pre-transplantation value (3.9 +/- 2.5 ms mmHg(-1) vs. 8.1 +/- 6.6 ms mmHg(-1) and 7.4 +/- 4.8 ms mmHg(-1), respectively; P = 0.042). Nevertheless, further analysis of individual data showed that only four patients exhibited a marked increase in their baroreflex slope 12 months after the liver transplantation whereas it remained decreased in the six others. CONCLUSIONS: These results confirm that the baroreflex sensitivity is depressed in end-stage liver disease in line with an autonomic nervous system imbalance. The liver transplantation reverses this disturbance only in some patients.

A simple method for generating a blood pressure-unit activity relationship for central cardiovascular neurons in the rat.

One way to identify central cardiovascular neurons is to consider their barosensitivity, for example by plotting changes in their single unit activity as a function of evoked changes in blood pressure. To simplify the genesis of such pressure-activity relationships, a coronary angioplasty catheter was threaded into the aorta of anaesthetized rats and the balloon inflated to raise the blood pressure mechanically. Here, such a procedure is exemplified for cardiac vagal motoneurons in the medulla oblongata in eight rats. This simplification bypasses potentially problematic surgery and minimizes deterioration of the animal.

Activity patterns of cardiac vagal motoneurons in rat nucleus ambiguus.

Extracellular recordings were made in the right nucleus ambiguus of urethane-anesthetized rats from 33 neurons that were activated at constant latency from the craniovagal cardiac branch. Their calculated conduction velocities were in the B-fiber range (1.6-13.8 m/s, median 4.2), and most (22/33) were silent. Active units were confirmed as cardiac vagal motoneurons (CVM) by the collision test for antidromic activation and by the presence of cardiac rhythmicity in their resting discharge (9/9). Brief arterial pressure rises of 20-50 mmHg increased the activity in five of five CVM by 0.1 +/- 0.02 spikes. s(-1). mmHg(-1) from a resting 3.8 +/- 1.2 spikes/s; they also recruited activity in two of four previously silent cardiac branch-projecting neurons. CVM firing was modulated by the central respiratory cycle, showing peak activity during inspiration (8/8). Rat CVM thus show firing properties similar to those in other species, but their respiratory pattern is distinct. These findings are discussed in relation to mechanisms of respiratory sinus arrhythmia.