Sepsis is a leading cause of mortality in critically ill patients. The pathophysiology of sepsis involves a highly complex and integrated response, including the activation of various cell types, inflammatory mediators, and the haemostatic system.
Recent evidence suggests an emerging role of the microcirculation in sepsis, necessitating a shift in our locus away Irom the macrohaemodynamics to ill icrohaemodynanmics in a septic patient. This review article provides a brief overview of the microcirculation, its assessment techniques, and specific therapies to resuscitate the microhaemodynamics.
Sepsis and its progression to severe sepsis, septic shock and multiple organ dysfunction syndrome is a major cause of ICU admissions and mortality1. Severe sepsis and septic shock may be characterized by a derangement in global cardiac indices typically leading to low peripheral resistance, which the body tries to compensate for by increasing the cardiac output. However, despite this increase in cardiac output, the tissues are unable to utilize oxygen as evidenced by the high lactate levels, deranged acid-base balance, and increased gastric carbon dioxide level. The presence of tissue hypoxia despite adequate systemic oxygen transport has been blamed on altered microhaemodynamics as well as in mitochondrial dysfunction during sepsis2. However, the relative contributions of disturbed microcirculation and impaired mitochondrial function for sepsis related tissue dysoxia are still debatable. The present review aims to highlight the former cause of tissue hypoxia in sepsis i.e., involvement of the microcirculation. It moves from recapitulating relevant anatomy of microcirculation, to its current role in pathophysiology of sepsis, optimization during sepsis and lastly the modalities for its assessment.
Microcirculatory perfusion as an endpoint
Much of the research pertaining to resuscitation during sepsis has focused on restoring the macrodynamics of circulation such as blood pressure, oxygen delivery and oxygen extraction ratio. The pathologic shunting occurring in the microcirculation is not depicted by systemic haemodynamic derived and oxygen derived variables. The difference between macrocirculation and microcirculation was recognized very early on10 when it was pointed that changes in total peripheral resistance could not provide information regarding local vascular resistance changes since “dilation in one vascular bed may be accompanied by constriction elsewhere”. Also, the cause of alterations in the macrohaemodynamics lies in the microcirculation e.g., the decrease in systemic vascular resistance and hypotension result from arteriolar vasodilatation and hypovolemia from capillary leak. Thus, it needs to be answered whether resuscitating the microcirculation rather than the macrocirculation will finally answer the quest for improving survival in sepsis.
There is previous evidence that resuscitating the macrohaemodynamics is not always associated with improved microhaemodynamics, organ function, or survival31–35. A study by LeDoux and colleagues35 observed the effect of norepinephrine on global haemodynamic parameters and measures of tissue oxygenation during septic shock. While the mean blood pressure increased from 65 to 85 mmHg along with expected increase in heart rate and cardiac index (p<0.05), there was no improvement in organ function or tissue oxygenation as evidenced by decrease in urine output, no change in capillary red blood cell velocity, fall in capillary blood flow and increase in gastric pCO2. The authors thus concluded that resuscitation of mean blood pressure or cardiac output alone in septic shock is inadequate. Microcirculatory independence from arterial blood pressure in septic shock has also been proven using direct imaging of microcirculation33,34. DeBacker et al33 reported a significant decrease in vessel density and proportion of small perfused vessels in septic patients, the alterations being more severe in non-survivors and were not related to the mean arterial pressure. Sakr and colleagues34 further explored these findings by studying the microcirculation in 49 septic patients. The small vessel perfusion was seen to improve rapidly in survivors as compared to non-survivors, with no difference in the global haemodynamic variables. Together with the evidence showing that organ function improves and mortality decreases when resuscitation boosts microcirculatory flow36, the microcirculation does appear to be a new target for resuscitation during sepsis6.
Assessment of microcirculation
Till date, there is no single objective gold standard to assess the microcirculation. In clinical practice, microcirculatory perfusion has been traditionally judged by the color, capillary refill and temperature of the distal parts of the body (i.e., finger, toes, earlobes and nose). Amongst the investigational modalities available to assess microcirculation, both indirect indicators as well as direct techniques exist6, even though any single objective reliable method is still not recognized. Indirect techniques involve measurement of ‘downstream’ global derivatives of microcirculatory dysfunction such as lactate, carbon dioxide, and oxygen saturation. The direct imaging of microcirculatory perfusion seems a superior approach to assessment of microcirculation. Invention of microscope is perhaps the single most important advancement in technology linked to discovering the microcirculation, since experimental investigation of the microcirculation began soon after its advent. Studies of human microcirculation began at the end of 19th century, with Hueter using a microscope with reflected light to investigate vessels on inner border of lower lip.
With several clinical and laboratory indicators of identifying hypoperf ision due to the microcirculation dysfunction being available, it is perhaps time to recognize shock in sepsis keeping tissue hypoperfusion as distinct from hypotension. A perfusion based scoring system has been proposed by Spronk et al97. It emphasizes the need of extending recognition of shock severity to include microcirculatory parameters, besides global haemodynamic and oxygen-derived parameters.
Therapy in shock should be aimed at optimizing cardiac function, arterial hemoglobin saturation, and tissue perfusion. This not only includes correction of hypovolemia, but the restoration of an evenly distributed microcirculatory flow and adequate oxygen transport as well. The role of vasodilators in recruiting the microcirculation will need to be looked into further.
Direct monitoring of sublingual microcirculation monitoring appears to be a promising endpoint for resuscitating the microcirculation. An integrative approach incorporating both macrocirculatory and microcirculatory haemodynamic data may indeed hold the answer to resuscitation in sepsis.
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D’OXYVA is the only fully noninvasive, completely painless over-the-skin microcirculatory solution that has been validated to significantly improve microcirculation.
D’OXYVA works to prevent sepsis, and resulting septic shock, using life-restoring molecule carbon dioxide (CO₂) and gentle vapor dissolved across the skin in a fast, painless, handheld 5-minute application — performed either in a clinical setting or in the comfort and privacy of your own home.