Andre Vercueil

High-altitude physiology and pathophysiology: implications and relevance for intensive care medicine

Cellular hypoxia is a fundamental mechanism of injury in the critically ill. The study of human responses to hypoxia occurring as a consequence of hypobaria defines the fields of high-altitude medicine and physiology. A new paradigm suggests that the physiological and pathophysiological responses to extreme environmental challenges (for example, hypobaric hypoxia, hyper-baria, microgravity, cold, heat) may be similar to responses seen in critical illness. The present review explores the idea that human responses to the hypoxia of high altitude may be used as a means of exploring elements of the pathophysiology of critical illness.

Changes in sublingual microcirculatory flow index and vessel density on ascent to altitude

We hypothesized that ascent to altitude would result in reduced sublingual microcirculatory flow index (MFI) and increased vessel density. Twenty‐four subjects were studied using sidestream dark‐field imaging, as they ascended to 5300 m; one cohort remained at this altitude (n= 10), while another ascended higher (maximum 8848 m; n= 14). The MFI, vessel density and grid crossings (GX; an alternative density measure) were calculated. Total study length was 71 days; images were recorded at sea level (SL), Namche Bazaar (3500 m), Everest base camp (5300 m), the Western Cwm (6400 m), South Col (7950 m) and departure from Everest base camp (5300 m; 5300 m‐b). Peripheral oxygen saturation  , heart rate and blood pressure were also recorded. Compared with SL, altitude resulted in reduced sublingual MFI in small (<25 μm; P < 0.0001) and medium vessels (26–50 μm; P= 0.006). The greatest reduction in MFI from SL was seen at 5300 m‐b; from 2.8 to 2.5 in small vessels and from 2.9 to 2.4 in medium‐sized vessels. The density of vessels <25 μm did not change during ascent, but those >25 μm rose from 1.68 (± 0.43) mm mm−2 at SL to 2.27 (± 0.57) mm mm−2 at 5300 m‐b (P= 0.005); GX increased at all altitudes (P < 0.001). The reduction in MFI was greater in climbers than in those who remained at 5300 m in small and medium‐sized vessels (P= 0.017 and P= 0.002, respectively). At 7950 m, administration of supplemental oxygen resulted in a further reduction of MFI and increase in vessel density. Thus, MFI was reduced whilst GX increased in the sublingual mucosa with prolonged exposure to hypoxia and was exaggerated in those exposed to extreme altitude.

Reduced coagulation at high altitude identified by thromboelastography

The impact of hypoxaemia on blood coagulation remains unclear despite use of a variety of measures to address the issue. We report the first use of thromboelastography (TEG) at high altitude to describe the dynamics of clot formation in whole blood samples. Seventeen healthy volunteers ascended to 5,300 m following an identical ascent profile; TEG measurements at 4,250 m and 5,300 m were compared with those from sea level. Peripheral oxygen saturation (SpO2) and haematocrit were also measured. Ascent resulted in a decline in SpO2 from 97.8 (± 1.2) % at sea level to 86.9 (± 3.3) % at 4,250 m and 79.5 (± 5.8) % at 5,300 m (p<0.001); haematocrit rose from 43.7 (± 2.8) % at sea level, to 46.7 (± 3.9) % and 52.6 (± 3.2) % at 4,250 m and 5,300 m, respectively (p<0.01). TEG reaction (R)-time and kinetic (K)-time were both increased at 5,300 m compared to sea level, 8.95 (± 1.37) minutes (min) to 11.69 (± 2.91) min (p=0.016) and 2.40 (± 0.66) min to 4.99 (± 1.67) min (p<0.001), respectively. Additionally the alpha (α)-angle was decreased from 57.7 (± 8.2) to 51.6 (± 6.4) (p<0.001). There was no change in maximum amplitude (MA) on ascent to altitude. These changes are consistent with an overall pattern of slowed coagulation at high altitude.

Extracorporeal membrane oxygenation for refractory hypoxemia after liver transplantation in severe hepatopulmonary syndrome: A solution with pitfalls

According to a recent publication by Nayyar et al., severe hypoxemia after liver transplantation (LT) in patients with hepatopulmonary syndrome (HPS) is not uncommon. According to a review of the literature and the authors’ local institutional experience, the prevalence could be as high as 12% with a mortality rate of 45%. Very severe preoperative hypoxemia, defined as a partial pressure of oxygen 50 mm Hg, and the presence of anatomical shunts were identified as predictors of this complication. Among the possible treatment strategies, the authors reported the use of inhaled vasodilator agents and systemic vasoconstrictors such as methylene blue to improve ventilation perfusion matching. The effectiveness of specific rescue ventilation strategies such as high-frequency oscillatory techniques and ventilation in the prone position remains unproven. We would like to propose another potentially beneficial treatment and bridging strategy: venovenous (V-V) extracorporeal membrane oxygenation (ECMO). Long-term ECMO support in this population after transplantation, solely for treating refractory shunt, has thus far not been reported in adults. Cannulation for ECMO after LT can also pose a significant challenge that depends on the configuration used. We have used ECMO in 6 patients (5 adults and 1 child) before and after LT since December 2012. Three patients required extracorporeal cardiac support, whereas the other 3 patients underwent V-V ECMO for hypoxemic respiratory failure. Ethical approval for the reporting of anonymous data was given by the South East London Research Ethics Committee.

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.

Sublingual microcirculatory blood flow and vessel density in Sherpas at high altitude

Anecdotal reports suggest that Sherpa highlanders demonstrate extraordinary tolerance to hypoxia at high altitude, despite exhibiting lower arterial oxygen content than acclimatized lowlanders. This study tested the hypothesis that Sherpas exposed to hypobaric hypoxia on ascent to 5,300 m develop increased microcirculatory blood flow as a means of maintaining tissue oxygen delivery. Incident dark-field imaging was used to obtain images of the sublingual microcirculation from 64 Sherpas and 69 lowlanders. Serial measurements were obtained from participants undertaking an ascent from baseline testing (35 m or 1,300 m) to Everest base camp (5,300 m) and following subsequent descent in Kathmandu (1,300 m). Microcirculatory flow index and heterogeneity index were used to provide indexes of microcirculatory flow, while capillary density was assessed using small vessel density. Sherpas demonstrated significantly greater microcirculatory blood flow at Everest base camp, but not at baseline testing or on return in Kathmandu, than lowlanders. Additionally, blood flow exhibited greater homogeneity at 5,300 and 1,300 m (descent) in Sherpas than lowlanders. Sublingual small vessel density was not different between the two cohorts at baseline testing or at 1,300 m; however, at 5,300 m, capillary density was up to 30% greater in Sherpas. These data suggest that Sherpas can maintain a significantly greater microcirculatory flow per unit time and flow per unit volume of tissue at high altitude than lowlanders. These findings support the notion that peripheral vascular factors at the microcirculatory level may be important in the process of adaptation to hypoxia.NEW & NOTEWORTHY Sherpa highlanders demonstrate extraordinary tolerance to hypoxia at high altitude, yet the physiological mechanisms underlying this tolerance remain unknown. In our prospective study, conducted on healthy volunteers ascending to Everest base camp (5,300 m), we demonstrated that Sherpas have a higher sublingual microcirculatory blood flow and greater capillary density at high altitude than lowlanders. These findings support the notion that the peripheral microcirculation plays a key role in the process of long-term adaptation to hypoxia.

Computed Tomographic Imaging in Peripheral VA-ECMO: Where Has All the Contrast Gone?

VENOARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION (VA–ECMO) is used increasingly as an emergency support tool for patients suffering from refractory cardiogenic shock of varying etiologies. According to the most recent Extracorporeal Life Support Organization (ELSO) statistics, 709 adult patients underwent VA-ECMO support in 2012 (Extracorporeal Life Support Registry Report, International Summary, January, 2013). The exact number of cases treated in a peripheral femoro-femoral configuration is not known. Although the authors assume that a small percentage of these patients underwent CT imaging, there are no reports they could find in the literature discussing the specific appearances of contrast distribution that have to be expected during extracorporeal circulatory support. Previous retrospective studies predominantly highlighted the clinical and diagnostic benefits of CT scanning as well as the safety of transfers in patients primarily supported in a venovenous (VV) configuration for treatment of refractory respiratory failure. During venovenous (VV) ECMO, contrast is drained into the extracorporeal circuit, however, subsequently returned to the right atrium through the return cannula; hence, only timing of imaging and the volume of contrast required will be affected. This is very different during VA support in which, at full flow, most of the contrast is drained into the extracorporeal circuit and subsequently returned to the aorta bypassing the lungs and the left heart. This gives rise to unique radiologic appearances akin to a large shunt that may cause confusion among clinicians who are unfamiliar with ECMO physiology.

Resuscitation fluids in trauma, part II: Which fluid should I give?

compartment interfaces, and changes in the interfaces during the pathophysiological processes of hypovolaemic shock is important. Total body water in man is approximately 60% of total body weight and is distributed within several compartments. The intracellular component is the largest, comprising about two-thirds of total body water (30 L). The extra-cellular fluid constitutes the remaining one-third of total body water (15 L), and may be subdivided further into two compartments: the intravascular compartment, with 3 L plasma and 2 L blood cells (strictly intracellular), and the interstitial compartment of approximately 12 L. Trauma may disturb the pattern of fluid distribution between compartments either by increasing the permeability of the barriers separating compartments, such as occurs during SIRS, or by altering compartment composition such as reducing blood volume during haemorrhage. Resuscitation fluids may be isotonic, hypotonic or hypertonic with respect to plasma. They may be either crystalloid or colloid solutions, and these factors will dictate their distribution with respect to the semipermeable membranes separating the different compartments of the body. The osmotic pressure generated by a solute is proportional to the number of molecules or ions of solute and to their charge characteristics, and is independent of solute molecular size. Solutes that pass freely across a semipermeable membrane do not generate any osmotic pressure, and are effectively a component of the solvent, with respect to that membrane. Water moves freely across a semi-permeable membrane and does so from an area of low osmolality to one of higher osmolality, and this movement continues until the osmotic pressures are equal on both sides of the membrane. Intravenous fluids are administered into the intravascular space contained within the vessel and capillary walls. The capillary walls are freely Trauma 2006; 8: 111–121

Resuscitation fluids in trauma 1: why give fluid and how to give it

Fluid resuscitation following trauma is necessary to restore compromised organ perfusion and hypoxic tissue damage. The activation of the Systemic Inflammatory Response Syndrome in response to both traumatic and subsequent hypoxic insults has implications for what represents the optimal fluid resuscitation strategy. There is no single resuscitation strategy that can be applied to all patients with traumatic injury. This article reviews the evidence available to help guide fluid therapy. A number of studies have suggested that timing of fluid therapy with respect to surgical intervention is crucial. Prior to definitive treatment of injury permissive hypotension confers advantage, particularly in the setting of penetrating trauma. The situation is less clear in cases of blunt trauma, where further studies comparing restrictive with liberal fluid regimes are required. The site of injury will also influence the strategy to be adopted. Following traumatic brain injury, maintenance of cerebral perfusion pressure is likely to be of overriding importance. Once definitive surgical control of haemorrhage has been achieved, fluid therapy to maximise stroke volume and cardiac output is advised. Following the development of established critical illness, goal-directed therapy may increase mortality.

Extracorporeal Membrane Oxygenation and Pediatric Liver Transplantation – “A step too far?” Results of a single center experience

Extracorporeal membrane oxygenation (ECMO) is an established rescue therapy for refractory hypoxemia. More recently, a potential role has emerged in the context of adult orthotopic liver transplantation (OLT), both as a preoperative or intraoperative emergency rescue technique to facilitate transplantation itself, or to enable recovery from severe acute respiratory failure in the postoperative period. Within the pediatric population, the published evidence of the use of ECMO in liver transplantation is limited to isolated case reports. Here we present a small series of 3 pediatric patients in whom venovenous (VV) ECMO was used to either facilitate emergency liver transplantation (ELT) in the context of preoperative refractory hypoxemia, or assist during postoperative severe respiratory failure unresponsive to conventional therapy. Ethics approval for the reporting of anonymous data was given by the South East London Research Ethics Committee.