Philip J. Hennis

Cardiopulmonary exercise testing for the evaluation of perioperative risk in non-cardiopulmonary surgery

The use of cardiopulmonary exercise testing (CPET) as a preoperative risk stratification tool for a range of non-cardiopulmonary surgery is increasing. The utility of CPET in this role is dependent on the technology being able to identify accurately and reliably those patients at increased risk of perioperative events when compared with existing risk stratification tools. This article identifies and reviews systematically the current literature regarding the use of CPET as a preoperative tool for stratifying risk in major non-cardiopulmonary surgery. Specifically, it focuses on evaluating the capacity of CPET variables to predict the risk of postoperative complications and mortality in comparison to other methods of risk assessment. Furthermore, the potential for combining results from CPET and non-CPET methods of risk prediction to enhance the capacity to identify high risk patients is considered. The review indicates that CPET can identify patients at increased risk of adverse perioperative outcomes. However, the selection of variables and threshold values to indicate high risk differ for different surgical procedures and underlying conditions. Furthermore, the available data suggest that CPET variables outperform alternative methods of preoperative risk stratification. Several studies also identify that CPET variables may be used in combination with non-CPET variables to increase perioperative risk prediction accuracy. These findings illustrate that CPET has the capacity to identify patients at increased risk of adverse outcome before a range of non-cardiopulmonary surgical procedures. Further research is required to optimise its use, potentially by combining CPET results with alternative methods of risk stratification.

Cardiopulmonary exercise testing predicts postoperative outcome in patients undergoing gastric bypass surgery

BACKGROUND For several types of non-cardiac surgery, the cardiopulmonary exercise testing (CPET)-derived variables anaerobic threshold (AT), peak oxygen consumption (VO2 peak), and ventilatory equivalent for CO(2) (VE/VCO2 ) are predictive of increased postoperative risk: less physically fit patients having a greater risk of adverse outcome. We investigated this relationship in patients undergoing gastric bypass surgery. METHODS All patients (<190 kg) who were referred for CPET and underwent elective gastric bypass surgery at the Whittington Hospital NHS Trust between September 1, 2009, and February 25, 2011, were included in the study (n=121). Fifteen patients did not complete CPET. CPET variables (VO2 peak, AT, and VE/VCO2 ) were derived for 106 patients. The primary outcome variables were day 5 morbidity and hospital length of stay (LOS). The independent t-test and Fishers exact test were used to test for differences between surgical outcome groups. The predictive capacity of CPET markers was determined using receiver operating characteristic (ROC) curves. RESULTS The AT was lower in patients with postoperative complications than in those without [9.9 (1.5) vs 11.1 (1.7) ml kg(-1) min(-1), P=0.049] and in patients with a LOS>3 days compared with LOS ≤ 3 days [10.4 (1.4) vs 11.3 (1.8) ml kg(-1) min(-1), P=0.023]. ROC curve analysis identified AT as a significant predictor of LOS>3 days (AUC 0.640, P=0.030). The VO2 peak and VE/VCO2 were not associated with postoperative outcome. CONCLUSIONS AT, determined using CPET, predicts LOS after gastric bypass surgery.

The physiological effects of hypobaric hypoxia versus normobaric hypoxia: a systematic review of crossover trials.

Much hypoxia research has been carried out at high altitude in a hypobaric hypoxia (HH) environment. Many research teams seek to replicate high-altitude conditions at lower altitudes in either hypobaric hypoxic conditions or normobaric hypoxic (NH) laboratories. Implicit in this approach is the assumption that the only relevant condition that differs between these settings is the partial pressure of oxygen (PO2), which is commonly presumed to be the principal physiological stimulus to adaptation at high altitude. This systematic review is the first to present an overview of the current available literature regarding crossover studies relating to the different effects of HH and NH on human physiology. After applying our inclusion and exclusion criteria, 13 studies were deemed eligible for inclusion. Several studies reported a number of variables (e.g. minute ventilation and NO levels) that were different between the two conditions, lending support to the notion that true physiological difference is indeed present. However, the presence of confounding factors such as time spent in hypoxia, temperature, and humidity, and the limited statistical power due to small sample sizes, limit the conclusions that can be drawn from these findings. Standardisation of the study methods and reporting may aid interpretation of future studies and thereby improve the quality of data in this area. This is important to improve the quality of data that is used for improving the understanding of hypoxia tolerance, both at altitude and in the clinical setting.

Metabolic basis to Sherpa altitude adaptation

Significance A relative fall in tissue oxygen levels (hypoxia) is a common feature of many human diseases, including heart failure, lung diseases, anemia, and many cancers, and can compromise normal cellular function. Hypoxia also occurs in healthy humans at high altitude due to low barometric pressures. Human populations resident at high altitude in the Himalayas have evolved mechanisms that allow them to survive and perform, including adaptations that preserve oxygen delivery to the tissues. Here, we studied one such population, the Sherpas, and found metabolic adaptations, underpinned by genetic differences, that allow their tissues to use oxygen more efficiently, thereby conserving muscle energy levels at high altitude, and possibly contributing to the superior performance of elite climbing Sherpas at extreme altitudes. The Himalayan Sherpas, a human population of Tibetan descent, are highly adapted to life in the hypobaric hypoxia of high altitude. Mechanisms involving enhanced tissue oxygen delivery in comparison to Lowlander populations have been postulated to play a role in such adaptation. Whether differences in tissue oxygen utilization (i.e., metabolic adaptation) underpin this adaptation is not known, however. We sought to address this issue, applying parallel molecular, biochemical, physiological, and genetic approaches to the study of Sherpas and native Lowlanders, studied before and during exposure to hypobaric hypoxia on a gradual ascent to Mount Everest Base Camp (5,300 m). Compared with Lowlanders, Sherpas demonstrated a lower capacity for fatty acid oxidation in skeletal muscle biopsies, along with enhanced efficiency of oxygen utilization, improved muscle energetics, and protection against oxidative stress. This adaptation appeared to be related, in part, to a putatively advantageous allele for the peroxisome proliferator-activated receptor A (PPARA) gene, which was enriched in the Sherpas compared with the Lowlanders. Our findings suggest that metabolic adaptations underpin human evolution to life at high altitude, and could have an impact upon our understanding of human diseases in which hypoxia is a feature.

Association between preoperative haemoglobin concentration and cardiopulmonary exercise variables: a multicentre study.

BackgroundPreoperative anaemia and low exertional oxygen uptake are both associated with greater postoperative morbidity and mortality. This study reports the association among haemoglobin concentration ([Hb]), peak oxygen uptake (V˙O2 peak) and anaerobic threshold (AT) in elective surgical patients.MethodsBetween 1999 and 2011, preoperative [Hb] and cardiopulmonary exercise tests were recorded in 1,777 preoperative patients in four hospitals. The associations between [Hb], V˙O2 peak and AT were analysed by linear regression and covariance.ResultsIn 436 (24.5%) patients, [Hb] was <12 g dl-1 and, in 83 of these, <10 g dl-1. Both AT and V˙O2 peak rose modestly with increasing [Hb] (r2 = 0.24, P <0.0001 and r2 = 0.30, P <0.0001, respectively). After covariate adjustment, an increase in [Hb] of one standard deviation was associated with a 6.7 to 9.7% increase in V˙O2 peak, and a rise of 4.4 to 6.0% in AT. Haemoglobin concentration accounted for 9% and 6% of the variation in V˙O2 peak and AT respectively.ConclusionsTo a modest extent, lower haemoglobin concentrations are independently associated with lower oxygen uptake during preoperative cardiopulmonary exercise testing. It is unknown whether this association is causative.

Isolated Generalized Tonic-Clonic Seizure at High Altitude in a Young Male Trekker with a Positive Family History of Seizure

An 18-year-old Caucasian male was trekking to Mount Everest base-camp (EBC) in Nepal during the spring of 2011. He normally lived at sea-level in the United Kingdom and had no previous medical history. His father had experienced one generalized tonic-clonic seizure at age 32, with no subsequent epileptiform events. The subject was in the control arm of a randomized controlled research study (n = 40) following a standardized ascent profile to EBC (Levett et al., 2010). Every morning he completed a Lake Louise AMS questionnaire (Roach et al., 1993) and had resting heart rate (HR), respiratory rate (RR), and peripheral oxygen saturations (Spo2) measured. Over 6 days, the subject had flown from Kathmandu (1300 meters) to Lukla (2800 meters) and trekked from Lukla to Pheriche (4250 meters). During this time, he reported no symptoms of AMS, whilst other research participants did experience symptoms (number of trekkers with AMS symptoms ranged between 0–9 per day). Additionally, the subject expressed no signs of high altitude cerebral edema (HACE), and recorded physiological variables that were similar to other study participants. At rest, on the morning of the seizure (7 day of trek), Spo2 was 85%, RR was 9 breaths.min , and HR was 55 beats.min 1 (vs. group means of 85%, 14 breaths.min , and 81 beats.min , respectively). The tonic-clonic seizure occurred in the absence of any obvious acute precipitating event in the presence of doctors at the Pheriche Himalayan Rescue Association clinic (4250 meters). The seizure was managed immediately with supplemental oxygen and 1000 mL of Dextrose Saline (4%/ 0.9%) intravenously. The seizure lasted approximately 1 minute and was followed by a 10 minute post-ictal phase characterized by drowsiness and confusion. Following recovery and a subsequent normal physical examination, the subject stated he had no memory of the episode, did not recall an aura prior to the event, and reported feeling previously well. He was repatriated to Kathmandu where an electroencephalogram and computed tomography of his head were both reported as ‘normal’ by attending specialists. He commenced a 10-day course of Lorazepam and returned to the UK, where cranial magnetic resonance imaging was reported as normal. He remains well 17 months post the event, and has had no subsequent seizures. This report highlights a young male with a family history of seizures, who experienced an isolated tonic-clonic seizure whilst hypoxemic at 4250 m. There was no evidence of AMS or HACE, and based on comparisons with his immediate trekking companions, cardiorespiratory physiological responses were normal for the altitude. Due to the limited amount of epidemiological data available, it is currently uncertain if high altitude per se is a trigger for epileptiform seizures. A number of anecdotal reports and small studies describe the occurrence of seizures at altitude and have suggested potential risk factors including sleep disturbance (Maa, 2010), hyperventilation (Daleau et al., 2006; Maa, 2011), and the direct effects of hypobaric hypoxia (Maa, 2011). Hypoxemia may have lowered the seizure threshold in this individual, something with potential implications for any person with either a personal or family history of seizure activity that is considering travelling to altitude. It is also possible that the occurrence of this seizure at altitude was coincidental; the rate of unprovoked seizures in a population from London has been reported at 57 per 100,000 per year (MacDonald et al., 2000). Given this uncertainty, this case report highlights the need for more robust epidemiological data collection to identify and quantify risk factors for high altitude seizures. Only through such studies will it be possible to establish whether altitude exposure per se increase the frequency of seizures and thereby refine advice for travellers planning ascents to high altitude.

The anion study: effect of different crystalloid solutions on acid base balance, physiology, and survival in a rodent model of acute isovolaemic haemodilution

Background: Commercially available crystalloid solutions used for volume replacement do not exactly match the balance of electrolytes found in plasma. Large volume administration may lead to electrolyte imbalance and potential harm. We hypothesised that haemodilution using solutions containing different anions would result in diverse biochemical effects, particularly on acid‐base status, and different outcomes. Methods: Anaesthetised, fluid‐resuscitated, male Wistar rats underwent isovolaemic haemodilution by removal of 10% blood volume every 15 min, followed by replacement with one of three crystalloid solutions based on acetate, lactate, or chloride. Fluids were administered in a protocolised manner to achieve euvolaemia based on echocardiography‐derived left ventrical volumetric measures. Removed blood was sampled for plasma ions, acid‐base status, haemoglobin, and glucose. This cycle was repeated at 15‐min intervals until death. The primary endpoint was change in plasma bicarbonate within each fluid group. Secondary endpoints included time to death and cardiac function. Results: During haemodilution, chloride‐treated rats showed significantly greater decreases in plasma bicarbonate and strong ion difference levels compared with acetate‐ and lactate‐treated rats. Time to death, total volume of fluid administered: chloride group 56 (3) ml, lactate group 62 (3) ml, and acetate group 65 (3) ml; haemodynamic and tissue oxygenation changes were, however, similar between groups. Conclusions: With progressive haemodilution, resuscitation with a chloride‐based solution induced more acidosis compared with lactate‐ and acetate‐based solutions, but outcomes were similar. No short‐term impact was seen from hyperchloraemia in this model.

Effects of dietary nitrate on respiratory physiology at high altitude: results from the Xtreme Alps study

Nitric oxide (NO) production plays a central role in conferring tolerance to hypoxia. Tibetan highlanders, successful high-altitude dwellers for millennia, have higher circulating nitrate and exhaled NO (ENO) levels than native lowlanders. Since nitrate itself can reduce the oxygen cost of exercise in normoxia it may confer additional benefits at high altitude. Xtreme Alps was a double-blinded randomised placebo-controlled trial to investigate how dietary nitrate supplementation affects physiological responses to hypoxia in 28 healthy adult volunteers resident at 4559 m for 1 week; 14 receiving a beetroot-based high-nitrate supplement and 14 receiving a low-nitrate ‘placebo’ of matching appearance/taste. ENO, vital signs and acute mountain sickness (AMS) severity were recorded at sea level (SL) and daily at altitude. Moreover, standard spirometric values were recorded, and saliva and exhaled breath condensate (EBC) collected. There was no significant difference in resting cardiorespiratory variables, peripheral oxygen saturation or AMS score with nitrate supplementation at SL or altitude. Median ENO levels increased from 1.5/3.0  mPa at SL, to 3.5/7.4 mPa after 5 days at altitude (D5) in the low and high-nitrate groups, respectively (p = 0.02). EBC nitrite also rose significantly with dietary nitrate (p = 0.004), 1.7–5.1  μM at SL and 1.6–6.3 μM at D5, and this rise appeared to be associated with increased levels of ENO. However, no significant changes occurred to levels of EBC nitrate or nitrosation products (RXNO). Median salivary nitrite/nitrate concentrations increased from 56.5/786 μM to 333/5,194  μM  with nitrate supplementation at SL, and changed to 85.6/641 μM and 341/4,553 μM on D5. Salivary RXNO rose markedly with treatment at SL from 0.55 μM to 5.70 μM. At D5 placebo salivary RXNO had increased to 1.90 μM whilst treatment RXNO decreased to 3.26 μM. There was no association with changes in any observation variables or AMS score. In conclusion, dietary nitrate supplementation is well tolerated at altitude and significantly increases pulmonary NO availability and both salivary and EBC NO metabolite concentrations. Surprisingly, this is not associated with changes in hemodynamics, oxygen saturation or AMS development.