Delineating Gastrointestinal Dysfunction Variants in Severe Burn Injury Cases: A Retrospective Case Series with Literature Review

Sriharsha Rapaka MD ^1,2

Priyankar Kumar Datta MD, DNB, DM ³

Shashikant Sharma MD, DM ^3,4

¹Intensive Care Medicine, St John of God Healthcare, Victoria, Australia

²Critical Care Medicine, All India Institute of Medical Sciences, New Delhi, India

³Anaesthesiology, Pain Medicine and Critical Care, All India Institute of Medical Sciences, New Delhi, India

⁴Critical Care Medicine, Jayaprabha Medanta Hospital, Patna, India

Abstract 

Background: Severe burns can significantly impact various organ systems, including the gastrointestinal (GI) system. GI complications are frequently observed in patients with over 20% total body surface area (TBSA) burn.

Objectives: This case series delves into the intricate phenomenology of post-burn GI dysfunction, challenging conventional cause-and-effect paradigms. Our aim is to discern, comprehend, and explore variables influencing positive and negative outcomes, laying the foundation for further research given the current heterogeneity in the literature.

Methods: Severe burn patients with GI dysfunction identified between April 1, 2022, and July 31, 2022, from the institutional database are included in this retrospective case-series, and comparisons were made across baseline and treatment conditions across participants. Data were collected on demographics, burn characteristics, complications, and treatment outcomes.

Results: We analysed 12 patients with severe burns and GI dysfunction and categorized them into two patterns: Pattern A, characterised by early onset symptoms, gastric and small bowel dilatation, and a relatively benign course with high recovery rates was observed in 6 patients; and Pattern B, characterised by late-onset symptoms, colonic dilatation, shock, and a high mortality rate due to megacolon was seen in 6 patients.

Conclusion: The post-burn GI dysfunction observed in our study is a complex interplay of multiple factors. Adequate fluid resuscitation, timely excision of necrotic tissue, staged food ingestion, specific nutrient administration, and appropriate use of antibiotics and judicious use of selective digestive decontamination (SDD) are essential strategies to prevent and treat this syndrome.

Introduction

Severe burns can have significant physiological impacts on the body, posing a risk to a patient's life that may be exacerbated by complications throughout the stages of treatment (1,2). Gastrointestinal (GI) complications are common in partial and full-thickness burns involving more than 20% TBSA and can include constipation, delayed gastric emptying, bacterial translocation, and sepsis, among others (2,3). While animal models suggest that burns delay gastric emptying and affect gut motility, the exact mechanism in humans is unknown (4,5). Probable causes could include large-volume fluid resuscitation, immobility, increased sympathetic drive secondary to pain, and dietary association with glutamine, opioids, and drugs such as tramadol and tapentadol. This study aims to describe two distinct patterns of bowel dysfunction observed in patients admitted with severe burns and discuss the impact of thermal injuries on gut motility and associated outcomes.

Methodology

Our study includes adult and paediatric patients with severe burns (>20% TBSA) and post-burn GI dysfunction, identified between April 1, 2022, and July 31, 2022. Data collection from discharge codes and chart reviews was conducted independently by two qualified, trained personnel for every participant from the medical records of eligible patients, employing anonymization protocols to uphold patient confidentiality during the entirety of the process. Data, including demographics, burn characteristics, complications, and response to treatment, were collected for the entire course of clinical care and subsequently compiled and reported. The burn unit at the hospital is staffed with highly skilled clinical staff members who have specialized training in treating severe burns. The assessment of treatments and data was supervised by an expert analyst at the faculty level. 

Case Descriptions

The long-term outcome of a burn injury dramatically depends on the quality of care received during the initial hours. However, the majority of initial burn care is administered outside of specialized burn centres. It is essential to comprehend the intricacies of Advanced Burn Life Support (ABLS) to ensure the patient's optimal outcome. The medical team provided comprehensive intensive care to manage the patients' GI dysfunction and a description of the management, and treatment approach is summarised below.

1. Symptoms: Patients with severe burns presented with symptoms such as diarrhoea, constipation, feed intolerance, abdominal distension, and hypoactive or diminished bowel sounds.
2. Workup for diarrhoea: Patients underwent a workup that included testing for C. difficile toxin and stool culture and sensitivity, which both came back negative.
3. Treatment for diarrhoea: Patients were treated with oral rehydration solution (ORS), probiotics, and racecadotril capsule (1.5mg/kg). Osmotic diarrhoea mostly resolved with reducing feed volume and protein content. In non-responders with suspected C. difficile infection presenting with fever, leucocytosis and pain abdomen, stool sample for toxin detection or culture was sent and oral metronidazole and, or oral vancomycin therapy was initiated. In patients who progressed to paralytic ileus, IV metronidazole along with oral vancomycin and vancomycin enema were administered.
4. Treatment for constipation: Patients received syrup lactulose or syrup sodium picosulfate, liquid paraffin and milk of magnesia. Additionally, prokinetic agents were administered, and if necessary, enemas were used.
5. Management of abdominal distension: In cases of abdominal distension, bowel decompression was performed by inserting a nasogastric tube with an intermittent suction system. This procedure aimed to reduce or resolve gastric dilatation, prevent vomiting and decrease the risk of aspiration associated with paralytic ileus.
6. Intra-abdominal pressure (IAP) monitoring: Patients with abdominal distension underwent regular IAP monitoring, typically every 4 hours using indirect measurement via the bladder. If IAP exceeded 12 mmHg and was accompanied by hypotension, decreased urine output, or a tense abdomen, more frequent measurements (every 2 hours) were performed. Foley's catheter was also checked for blockage in case of increased IAP values. Monitoring continued until IAP levels dropped below 10 mmHg for several hours, along with clinical improvement.
7. Stress ulcer prophylaxis and thromboprophylaxis: Patients above the age of 3 received pantoprazole for stress ulcer prophylaxis. Additionally, adult patients received injection Enoxaparin (1mg/kg) for thromboprophylaxis and mechanical prophylaxis. These measures were continued until patients achieved full ambulation.
8. Antibiotics: Antibiotics were initiated only when signs of infection were observed, based on clinical assessment and monitoring of laboratory trends. Once definitive evidence of microbial growth from blood, urine, and wound cultures was obtained, culture-based antibiotics were started.
9. Source control: Whenever necessary, the surgical team performed source control procedures to address and manage the underlying cause.

Patient Characteristics

Patients were separated into two patterns based on their clinical characteristics and outcomes (Table 1) and abdominal X-rays (Table 2).

Table 1. Comparison of the Two Patterns of Presentation (to view Table 1 in a new and separate window click here)

• AKI=acute kidney injury

Table 2. Abdominal X-ray Patterns (to view Table 2 in a new and separate window click here)

Additional patient characteristics of pattern A and B are shown tables 3 and 4.

Table 3. Clinical Characteristics, Laboratory, and Imaging Findings of Patients with Pattern A GI Dysfunction (to view Table 3 in a new and separate window click here)

• TBSA=total burn surface area
• SOFA=Sequential Organ Failure Assessment Score

Table 4. Clinical Characteristics, Laboratory, and Imaging Findings of Patients with Pattern B GI Dysfunction (to view Table 4 in a new and separate window click here)

The two groups differed in baseline characteristics. The first group had a smaller median TBSA compared to the second group (32.5% vs 42.5%). Additionally, the first group comprised primarily paediatric patients, and their GI dysfunction developed earlier (median day 3 vs day 10), with a lower median SOFA score (0 vs 1). The second group had colonic dilatation in addition to gastric and small bowel dilatation, and all patients had signs and, or evidence of infection and were on antibiotics by the time they developed GI dysfunction. The median serum potassium levels were also slightly different between the two groups (3.8 vs 4.2). Notably, there were more deaths in the second group (50%) compared to the first group, where most patients recovered and were shifted to a step-down unit.

Discussion

The stress response, metabolic changes, and nutritional deficiencies primarily cause most gastrointestinal (GI) issues associated with burn injuries. If not promptly recognized and appropriately treated, these complications can lead to severe consequences, including fatal haemorrhage or perforation. Implementing early prophylactic measures during the post-burn period is crucial to prevent these outcomes. One common complication of thermal injuries is gastric distention and dysfunction.

Studies have shown that gastric emptying is significantly reduced by approximately 37-42% at 6 hours after a burn (4-6). In our study, we observed early gastric dilation upon admission. Burn injuries also affect the standard slow wave frequency in the stomach, increasing the occurrence of bradygastria (7). However, patients who arrived at the emergency department within 2 hours of the burn injury and received timely resuscitation mostly remained asymptomatic. Radiological evidence revealed gastric dilation, which eventually resolved during their hospital stay.

Animal studies have demonstrated that small intestinal transit time is significantly decreased in burn injury models compared to control groups at 2 hours (8,9) and 6 hours post-burn (5,6,9,10). In our study, we observed early small bowel dilation and ileus during the ICU stay. Chen et al conducted a study with rat models, revealing that the gastrointestinal motility in burn-injured rats treated with saline is notably higher compared to untreated burn-injured rats (11). This finding aligns with our observations, as most patients who arrived early and received timely resuscitation showed resolution of bowel dilation.

Colonic transit time was delayed compared to the control group in burn injury patients (5,12).  We could not find any literature on this topic in human subjects, highlighting the need for prospective studies. We noticed colonic involvement in symptomatic patients approximately one week after the burn injury. In cases of severe abdominal distension, dilated bowel loops, and feed intolerance, supplemental parenteral nutrition/TPN was administered. Early fluid resuscitation within 2 hours of a thermal injury is crucial in preventing multiple organ failure and mortality (18).

As described above, "Pattern A" patients experienced early symptoms during their ICU stay, showed minimal signs of infection, and had a relatively milder course with a lower mortality rate compared to "Pattern B" patients. Pattern B patients presented later, experienced more complications, and had higher morbidity and mortality rates. Dysmotility in these patients could be attributed to sepsis, opioids, or antibiotics. We tested for C. difficile toxin and culture, which came back negative. Immobility, opioid use, pain, and dietary glutamine are common causes of GI dysfunction in both patient groups. Incremental fentanyl infusion was administered to all patients within 24-48 hours of the injury. Breakthrough and procedural pain were managed with sub-anaesthetic doses of IV ketamine and IV fentanyl. Patients presenting with Pattern B symptoms were often prescribed slow-release oral tramadol/oral tapentadol/ pregabalin formulations to supplement or replace opioids due to concerns about constipation, tolerance, and addiction. Opioids could exacerbate GI symptoms like vomiting and constipation (14). Tramadol was found to delay colonic transit but did not affect upper gastrointestinal transit.¹⁵ Tapentadol, on the other hand, provided analgesia with a more tolerable side effect profile and resulted in less deterioration of gastrointestinal function and symptoms compared to standard opioids (16,17). However, results from different studies on tapentadol’ s effects on gastric emptying and bowel function are inconsistent, making its routine use in severe burns unclear (18,19). NSAIDs are effective for mild to moderate burns, but opioids are preferred in severe cases due to acute kidney injury (AKI) concerns. AKI is common in severe burns and an independent mortality risk factor. While opioids and NSAIDs may have contributed to large bowel dysmotility in Pattern B patients, a causal relationship cannot be established.

Burn-injured patients often experience acute and chronic neuropathic pain. Pregabalin has shown efficacy in reducing neuropathic pain and improving sleep but may cause constipation (20,21). Stress ulcer prophylaxis with pantoprazole was administered to patients above three years of age. Short-term treatment with proton pump inhibitors (PPIs) has been reported to delay gastric emptying of solid meals in healthy individuals (22). The effects of PPIs on liquid emptying are inconsistent (23). Prolonged gastric residence of PPIs due to delayed emptying may impact their pharmacological effectiveness, which can be clinically relevant in managing conditions such as GERD, functional dyspepsia, and diabetes (24). However, routine administration of PPIs in severe burn patients is not recommended. Although a systematic review and meta-analysis suggested a potential correlation between the usage of proton pump inhibitors (PPIs) and a heightened likelihood of contracting Clostridium difficile infection (CDI), we did not find any substantiating evidence of CDI (25). Further high-quality and prospective studies are needed to establish a causal relationship.

Major burns trigger an inflammatory response and catabolism, which can lead to severe nutrition deficiencies when combined with burn wound nutrient losses. These deficiencies can impair immune function and wound healing and increase the risk of organ injury and mortality (26). Sepsis causes dysbiosis and bacterial translocation (27). Severe burn patients frequently experience sepsis-induced ileus (28). Early and staged enteral nutrition has been shown to reduce gram-negative bacteraemia in burn patients and promote a healthy intestinal microenvironment (29-32). Caloric requirements were calculated using the Curreri formula for adults and Curreri junior formula for paediatric patients. However, as the formula often overestimates caloric needs, a target of 70-80% of the calculated requirement was set. Using continuous feeding bags, oral and/or nasogastric feeding was initiated from day 1 in the ICU. Post-pyloric feeding was administered to patients with feed intolerance or high gastric residual volume. Micronutrients and trace elements were supplemented, and glutamine and fibre were added to the diet for adult patients. Glutamine stimulates the release of glucagon-like peptide-1, which increases postprandial insulin secretion and slows gastric emptying (33). Current recommendations support using glutamine in severe burn patients due to promising evidence and minimal adverse effects. The RE-ENERGIZE trial showed mortality at 6 months was 17.2% in the glutamine group and 16.2% in the placebo group (hazard ratio for death, 1.06; 95% CI, 0.80 to 1.41) and no substantial between-group differences in serious adverse events (26).

We hypothesize that prudent utilization of selective digestive decontamination (SDD) may reduce infections and improve survival in severe burn patients (34). In a randomized trial, SDD demonstrated improved survival. However, according to a meta-analysis, enteral antibiotic use did not reduce mortality in severe burn patients, which aligns with our findings (35).

Managing wounds in the early stages and providing postoperative care after skin grafting pose challenges in patients with extensive burns. Effective use of negative pressure wound therapy (NPWT) can facilitate better wound healing and reduce infections. Patients with burns involving the perineum and genitalia present particular challenges due to increased wound infections, graft loss, and sepsis caused by dressing soiling (36-38). We hypothesize that faecal management systems might reduce infections by diverting faeces and improving personal hygiene in severe burn patients. A retrospective study found a survival benefit with no significant complications associated with faecal management systems (39).

Limitations

Our study is a retrospective case series that has inherent constraints. Our study lacked a control group. Selection bias and treatment assignment bias cannot be ruled out. These unregulated and unidentified factors of variation have the potential to influence the general applicability of the study's outcomes. Further prospective studies are needed to establish causal associations.

Conclusions 

The first pattern of patients, primarily children without underlying health conditions, appeared to have experienced bowel dysfunction as a stress response amplified using PPIs. Diarrhoea in these cases was not due to an infection, and excessive sympathetic activity could be the contributing factor. On the other hand, the second pattern of patients, primarily adults with comorbidities, were seriously ill and received a combination of antibiotics, opioids, and gabapentin. These patients were also experiencing sepsis and sepsis-induced ileus, which is common in individuals with severe burns. In this group, diarrhoea could be caused by an infectious or non-infectious agent, and while testing for C. difficile was negative, there may have been delays in the transportation and analysis of stool samples that resulted in false negative results. It is important to note that repeating the tests is unlikely to improve the sensitivity of the results (40).Top of Form

Learning Points

1. Post-burn gastrointestinal issues are caused by a combination of factors that disrupt the balance of gut microbes leading to sepsis and multiple organ dysfunction syndrome (MODS).
2. Further prospective studies are needed to establish the effect of tramadol, tapentadol and pregabalin on GI system in severe burns.
3. The regular use of PPIs may worsen the impact of severe burns on the gut.
4. Managing serious burns necessitates a collaborative strategy encompassing prompt and effective fluid replacement, timely removal of deceased tissue, cautious initiation of nutrition, targeted use of antibiotics, and thoughtful application of selective digestive decontamination (SDD) to prevent gastrointestinal complications and reduce mortality.
5. Faecal management systems and negative pressure wound therapy (NPWT) can help to improve wound care and hygiene in patients with perineal burns.

References

1. Jeschke MG, Pinto R, Kraft R, Nathens AB, Finnerty CC, Gamelli RL, Gibran NS, Klein MB, Arnoldo BD, Tompkins RG, Herndon DN; Inflammation and the Host Response to Injury Collaborative Research Program. Morbidity and survival probability in burn patients in modern burn care. Crit Care Med. 2015 Apr;43(4):808-15. [CrossRef] [PubMed]
2. Jonason AM. Complications of burn injury. Occup Health Nurs. 1983 Jul;31(7):24-8. [CrossRef] [PubMed]
3. Czaja AJ, McAlhany JC, Pruitt BA Jr. Acute gastroduodenal disease after thermal injury. An endoscopic evaluation of incidence and natural history. N Engl J Med. 1974 Oct 31;291(18):925-9. [CrossRef] [PubMed]
4. Sallam HS, Kramer GC, Chen JD. Gastric emptying and intestinal transit of various enteral feedings following severe burn injury. Dig Dis Sci. 2011 Nov;56(11):3172-8. [CrossRef] [PubMed]
5. Sallam HS, Oliveira HM, Gan HT, Herndon DN, Chen JD. Ghrelin improves burn-induced delayed gastrointestinal transit in rats. Am J Physiol Regul Integr Comp Physiol. 2007 Jan;292(1):R253-7. [CrossRef] [PubMed]
6. Oliveira HM, Sallam HS, Espana-Tenorio J, Chinkes D, Chung DH, Chen JD, Herndon DN. Gastric and small bowel ileus after severe burn in rats: the effect of cyclooxygenase-2 inhibitors. Burns. 2009 Dec;35(8):1180-4. [CrossRef] [PubMed]
7. Sallam HS, Oliveira HM, Liu S, Chen JD. Mechanisms of burn-induced impairment in gastric slow waves and emptying in rats. Am J Physiol Regul Integr Comp Physiol. 2010 Jul;299(1):R298-305. [CrossRef] [PubMed]
8. Alican I, Coşkun T, Yeğen C, Aktan AO, Yalin R, Yeğen BC. The effect of thermal injury on gastric emptying in rats. Burns. 1995 May;21(3):171-4. [CrossRef] [PubMed]
9. Unlüer EE, Alican I, Yeğen C, Yeğen BC. The delays in intestinal motility and neutrophil infiltration following burn injury in rats involve endogenous endothelins. Burns. 2000 Jun;26(4):335-40. [CrossRef] [PubMed]
10. Oktar BK, Cakir B, Mutlu N, Celikel C, Alican I. Protective role of cyclooxygenase (COX) inhibitors in burn-induced intestinal and liver damage. Burns. 2002 May;28(3):209-14. [CrossRef] [PubMed]
11. Chen CF, Chapman BJ, Munday KA, Fang HS. The effects of thermal injury on gastrointestinal motor activity in the rat. Burns Incl Therm Inj. 1982 Nov;9(2):142-6. [CrossRef] [PubMed]
12. Gan HT, Chen JD. Roles of nitric oxide and prostaglandins in pathogenesis of delayed colonic transit after burn injury in rats. Am J Physiol Regul Integr Comp Physiol. 2005 May;288(5):R1316-24. [CrossRef] [PubMed]
13. Barrow RE, Jeschke MG, Herndon DN. Early fluid resuscitation improves outcomes in severely burned children. Resuscitation. 2000 Jul;45(2):91-6. [CrossRef] [PubMed]
14. Melchior C, Desprez C, Wuestenberghs F, Leroi AM, Lemaire A, Goucerol G. Impact of Opioid Consumption in Patients With Functional Gastrointestinal Disorders. Front Pharmacol. 2020 Dec 21;11:596467. [CrossRef] [PubMed]
15. Wilder-Smith CH, Bettiga A. The analgesic tramadol has minimal effect on gastrointestinal motor function. Br J Clin Pharmacol. 1997 Jan;43(1):71-5. [CrossRef] [PubMed]
16. Singh DR, Nag K, Shetti AN, Krishnaveni N. Tapentadol hydrochloride: A novel analgesic. Saudi J Anaesth. 2013 Jul;7(3):322-6. [CrossRef] [PubMed]
17. Etropolski M, Kelly K, Okamoto A, Rauschkolb C. Comparable efficacy and superior gastrointestinal tolerability (nausea, vomiting, constipation) of tapentadol compared with oxycodone hydrochloride. Adv Ther. 2011 May;28(5):401-17. [CrossRef] [PubMed]
18. Mark EB, Nedergaard RB, Hansen TM, Nissen TD, Frøkjaer JB, Scott SM, Krogh K, Drewes AM. Tapentadol results in less deterioration of gastrointestinal function and symptoms than standard opioid therapy in healthy male volunteers. Neurogastroenterol Motil. 2021 Nov;33(11):e14131. [CrossRef] [PubMed]
19. Jeong ID, Camilleri M, Shin A, et al. A randomised, placebo-controlled trial comparing the effects of tapentadol and oxycodone on gastrointestinal and colonic transit in healthy humans. Aliment Pharmacol Ther. 2012 May;35(9):1088-96. [CrossRef] [PubMed]
20. Gray P, Kirby J, Smith MT, Cabot PJ, Williams B, Doecke J, Cramond T. Pregabalin in severe burn injury pain: a double-blind, randomised placebo-controlled trial. Pain. 2011 Jun;152(6):1279-1288. [CrossRef] [PubMed]
21. Toth C. Pregabalin: latest safety evidence and clinical implications for the management of neuropathic pain. Ther Adv Drug Saf. 2014 Feb;5(1):38-56. [CrossRef] [PubMed]
22. Kurt A, Altun A, Bağcivan I, Koyuncu A, Topcu O, Aydın C, Kaya T. Effects of proton pump inhibitors and h(2) receptor antagonists on the ileum motility. Gastroenterol Res Pract. 2011;2011:218342. [CrossRef] [PubMed]
23. Sanaka M, Yamamoto T, Kuyama Y. Effects of proton pump inhibitors on gastric emptying: a systematic review. Dig Dis Sci. 2010 Sep;55(9):2431-40. [CrossRef] [PubMed]
24. Baron JH. The pharmacology of gastric acid. Scand J Gastroenterol Suppl. 1983;18(87):7-23.
25. Trifan A, Stanciu C, Girleanu I, Stoica OC, Singeap AM, Maxim R, Chiriac SA, Ciobica A, Boiculese L. Proton pump inhibitors therapy and risk of Clostridium difficile infection: Systematic review and meta-analysis. World J Gastroenterol. 2017 Sep 21;23(35):6500-6515. [CrossRef] [PubMed]
26. Wischmeyer PE. Glutamine in Burn Injury. Nutr Clin Pract. 2019 Oct;34(5):681-687. [CrossRef] [PubMed]
27. Fay KT, Ford ML, Coopersmith CM. The intestinal microenvironment in sepsis. Biochim Biophys Acta Mol Basis Dis. 2017 Oct;1863(10 Pt B):2574-2583. [CrossRef] [PubMed]
28. Kirksey TD, Moncrief JA, Pruitt BA Jr, O'Neill JA Jr. Gastrointestinal complications in burns. Am J Surg. 1968 Nov;116(5):627-33. [CrossRef] [PubMed]
29. Huang HH, Lee YC, Chen CY. Effects of burns on gut motor and mucosa functions. Neuropeptides. 2018 Dec;72:47-57. [CrossRef] [PubMed]
30. He W, Wang Y, Wang P, Wang F. Intestinal barrier dysfunction in severe burn injury. Burns Trauma. 2019 Jul 26;7:24. [CrossRef] [PubMed]
31. Earley ZM, Akhtar S, Green SJ, et al. Burn Injury Alters the Intestinal Microbiome and Increases Gut Permeability and Bacterial Translocation. PLoS One. 2015 Jul 8;10(7):e0129996. [CrossRef} [PubMed]
32. Xiao SC, Zhu SH, Xia ZF, Lu W, Wang GQ, Ben DF, Wang GY, Cheng DS. Prevention and treatment of gastrointestinal dysfunction following severe burns: a summary of recent 30-year clinical experience. World J Gastroenterol. 2008 May 28;14(20):3231-5. [CrossRef] [PubMed]
33. Du YT, Piscitelli D, Ahmad S, Trahair LG, Greenfield JR, Samocha-Bonet D, Rayner CK, Horowitz M, Jones KL. Effects of Glutamine on Gastric Emptying of Low- and High-Nutrient Drinks in Healthy Young Subjects-Impact on Glycaemia. Nutrients. 2018 Jun 7;10(6):739. [CrossRef] [PubMed]
34. de La Cal MA, Cerdá E, García-Hierro P, van Saene HK, Gómez-Santos D, Negro E, Lorente JA. Survival benefit in critically ill burned patients receiving selective decontamination of the digestive tract: a randomized, placebo-controlled, double-blind trial. Ann Surg. 2005 Mar;241(3):424-30. [CrossRef] [PubMed]
35. Rubio-Regidor M, Martín-Pellicer A, Silvestri L, van Saene HKF, Lorente JA, de la Cal MA. Digestive decontamination in burn patients: A systematic review of randomized clinical trials and observational studies. Burns. 2018 Feb;44(1):16-23. [CrossRef] [PubMed]
36. Gómez-Ortega V, Vergara-Rodriguez MJ, Mendoza B, García T. Effect of Negative Pressure Wound Therapy in Electrical Burns. Plast Reconstr Surg Glob Open. 2021 Feb 17;9(2):e3383. [CrossRef] [PubMed]
37. Teng SC. Use of negative pressure wound therapy in burn patients. Int Wound J. 2016 Sep;13 Suppl 3(Suppl 3):15-8. [CrossRef] [PubMed]
38. Kantak NA, Mistry R, Varon DE, Halvorson EG. Negative Pressure Wound Therapy for Burns. Clin Plast Surg. 2017 Jul;44(3):671-677. [CrossRef] [PubMed]
39. Farroha A, Frew Q, Philp B, Dziewulski P. Improvement of survival in patients with extensive burns involving the perineum with use of a faecal management system. Ann Burns Fire Disasters. 2014 Mar 31;27(1):14-6. [PubMed]
40. Bagdasarian N, Rao K, Malani PN. Diagnosis and treatment of Clostridium difficile in adults: a systematic review. JAMA. 2015 Jan 27;313(4):398-408. [CrossRef] [PubMed]

Cite as: Rapaka S, Datta PK, Sharma S. Delineating Gastrointestinal Dysfunction Variants in Severe Burn Injury Cases: A Retrospective Case Series with Literature Review. Southwest J Pulm Crit Care Sleep. 2024;28(3):40-48. doi: https://doi.org/10.13175/swjpccs006-24 PDF 

Essentials of Airway Management: The Best Tools and Positioning for First-Attempt Intubation Success

Evan D. Schmitz MD

Pulmonary and Critical Care Medicine

Abstract

Head position during endotracheal intubation affects first-attempt success, as does the different tools available and the location. It is important to be skilled in the operation of a variety of laryngoscopes (video or direct) as well as introducers (plastic/steel stylets and bougies). Difficult airways should always be anticipated and proper preparation such as upper airway assessment performed. The following is a review of endotracheal intubations performed outside of the operating room.

Objectives

• Discuss how different locations in the hospital can affect endotracheal intubation success.
• Learn the difference between simple head positioning and the sniffing position and why one should be chosen over the other. MRI images of the head and neck in each position will be reviewed.
• Learn about different types of laryngoscope blades.
• Understand the dangers of video laryngoscopy as well as the benefits and when to choose direct laryngoscopy.
• Define endotracheal intubation first-attempt success.
• The benefits of using a bougie as opposed to a stylet to increase first-attempt success rate with a review of the supportive literature.
• Case presentations.

Abbreviations

• AF – atrial fibrillation
• ARDS – acute respiratory distress syndrome
• BiPAP – bilevel positive airway pressure
• CAD – coronary artery disease
• COPD – chronic obstructive pulmonary disease
• Ó – delta
• DM – diabetes mellitus
• DVT – deep vein thrombosis
• ED – emergency department
• ETT – endotracheal tube
• FiO2 – fraction of inspired oxygen
• HFNC – high flow nasal canula
• HTN – hypertension
• ICU – intensive care unit
• LA – laryngeal axis
• LV – line of vision
• MRI – magnetic resonance imaging
• NIDDM – non-insulin dependent diabetes mellitus
• NRB – non-rebreather mask
• OA – oral axis
• OR – operating room
• OSA – obstructive sleep apnea
• PA – pharyngeal axis
• PCO2 – partial pressure of carbon dioxide
• PE – pulmonary embolism
• RCA – right coronary artery
• SpO2 – pulse oximeter oxygen saturation
• Sz – seizure

Introduction

Ideal positioning can make the difference between a successful endotracheal intubation or death. Many times, intubations are performed in emergency situations, and positioning is not always ideal depending on the type of surface. In the OR, ideal conditions exist regarding adequate supplies and time (1). Conditions can be very different outside of the operating room (OR) especially during a code blue. The average time of intubation is 37 seconds in the emergency department (ED) (2). During the COVID-19 pandemic, intubations were being performed as quickly as 15 seconds in the intensive care unit (ICU) to prevent cardiac arrest in patients with severe adult respiratory distress syndrome (ARDS) (3).

Hospital beds are cumbersome and can cause poor positioning making intubation difficult. If possible, it is always a good idea to have a few towels available to help with head positioning. Towels can be rolled up and placed between the shoulder blades to aid in simple head extension. Towels can also be used to flex the neck on the chest and extend the head on the neck into the sniffing position. Pillows can be added if needed in morbidly obese patients.

Previous studies published in the Journal of Anesthesia comparing head positioning with regards to line of vision (LV), oral axis (OA), pharyngeal axis (PA), and laryngeal axis (LA) proved that all axes can never be perfectly aligned (Figure 1) (4). The same authors concluded that routine use of the sniffing position appears to provide no significant advantage over simple head extension for tracheal intubation (5).

The sniffing position improved glottic exposure in 18% of patients and worsened it in 11% in comparison with simple head extension in patients intubated in the operating room. Multivariant analysis showed that patients with reduced neck mobility and obesity did better in the sniffing position.

The angle between the LV to the LA, ó, decreases significantly when placed in simple head extension (B) and the sniffing position (C) compared with neutral positioning (A) (Figure 1). In simple head extension ó is the smallest approximating 20^o. The smaller the ó, the easier it is to access the glottis. Bougie introducers like the AIROD® telescopic steel bougie with a 20^o bend at the proximal end as well as elastic bougies with a coude (bent) tip allow easy transition from the LV to the laryngeal axis LA in simple head extension Figure 2 (6-10).

Figure 1.  Evaluation of the four axes (mouth axis [MA], pharyngeal axis [PA], laryngeal axis [LA], line of vision [LV] and the α, β, and ό angles in the three positions (4).

Figure 2. AIROD® aligned perfectly with the laryngeal view (LV) with the head in simple extension. Transition to the laryngeal axis (LA) is easy due to the specialized 20^o tip.

The different video laryngoscopes all offer indirect views of the glottis (Figure 3).

 

Figure 3. Different types of video and direct laryngoscopes.

For those on C-spine precautions, a hyperangulated Glidescope® or C-MAC® can help with the acute angles involved without the need for significant neck movement. Although video laryngoscopes may improve the view of the glottis because they do not guarantee a direct pathway to the vocal cords, disaster may occur during intubation. Additional tools and expertise should be available immediately because once sedatives and paralytics are given you may no longer be able to ventilate the patient.

In 2017 Baptiste et al. (11) published a study showing that severe life-threatening complications were higher in those ICU patients who were intubated using video laryngoscopy 9.5% vs 2.8% in those who were intubated with direct laryngoscopy with the numbers needed to harm of 14.6. Blood, emesis, secretions, damaged screen, and sudden battery failure can all obscure the video images, complicating intubation with video devices. It is therefore recommended that operators be comfortable using direct laryngoscopes as well as bougies in case of video device failures.

Prior to intubation, airway assessment should be performed to determine whether a difficult airway may be present. If any of the following characteristics are present, then a difficult airway should be expected and precautions taken:

• Mouth opening < 3.5 cm
• Thyromental distance < 6.5 cm
• BMI > 30 kg/m²
• Amplitude of head and neck movement < 80^o
• Mallampati score > 3
• Cormack and Lehane classification > 2

Figure 4. Mallampati scores classes 1-4 and Cormack and Lehane classification grades 1-4.

In addition to these measurements, a difficult airway is present if the airway is obstructed by emesis, blood, foreign object or swelling; if the patient has a short neck, large tongue, facial trauma; or if cervical spine immobilization is needed.

Increased complications arise during intubation when a difficult airway is present, especially in an unstable patient. Adverse events related to endotracheal intubation in the ED have been reported at 12% (11). Only 70% of patients intubated in the ICU are successfully intubated upon first-attempt (12). A successful first-attempt intubation is defined as the placement of an endotracheal tube into the trachea upon the initial insertion of the laryngoscope into the oropharynx. If the laryngoscope must be removed and a second-attempt performed, it is considered a failure. Failure to intubate with the first-attempt contributes considerably to morbidity and mortality (13).

The choice of the correct endotracheal introducer can make the difference between first-pass success and failure (Figure 5).

Figure 5. Types of airway introducers.

The standard endotracheal tube stylet is used most often during direct laryngoscopy. This stylet may be bent when used with a curved Macintosh blade or without a bend when used with a straight Miller blade. The former is the most common method. An elastic bougie has an advantage over the standard stylet as it can be placed through the vocal cords and into the trachea, allowing better access especially with anterior airways during direct laryngoscopy with a Macintosh or Miller blade.

The BEAM (Bougie Use in Emergency Airway Management) trial is attracting renewed interest in intubation with a bougie rather than a stylet (2). In the BEAM trial, first-attempt success using an elastic bougie was compared to a stylet during laryngoscopy in an emergency department.

First-attempt success was achieved in 98% of patients compared to 87% in all patients. In patients with at least one difficult airway characteristic, first-attempt success using an elastic bougie was 96% compared to 82% using a stylet.

In the First-Attempt Endotracheal Intubation Success Rate Using a Telescoping Steel Bougie (3), intubation first-attempt success rate was 97% in the ICU. Subgroup analysis of first-attempt intubation success using the AIROD® to intubate in patients with a difficult airway was 96%.

The average time to intubate was 15 seconds. During multiple intubations, the AIROD® was used to lift the epiglottis and move excess oropharyngeal tissue, improving the view of the glottis without causing any trauma to the airway (Figure 6).

Figure 6. Video of AIROD® lifting the epiglottis.

The hyperangulated Glidescope® stylet can be used with the Glidescope®, curved Macintosh blade, and C-MAC® blade. The AIROD® can be used with any direct or video laryngoscopy in any configuration: curved, hyperangulated, or straight.

The elastic bougie cannot make the acute turn required with hyperangluated laryngoscopes and should be avoided with this device unless the hyperangulated Glidescope® stylet is placed first and becomes caught up on the superior angle of the vocal cords. If this occurs, leave the Glidescope® in position and gently remove the hyperangulated Glidescope® stylet. While maintaining the acute angle, introduce an elastic bougie into the ETT and advance the tip into the trachea. Then slide the ETT down the bougie and into the trachea. 

An alternative is to use the AIROD® steel bougie from the beginning, along with the Glidescope®. Load an ETT from the bulbous tip of the AIROD®, then shape to accommodate airway anatomy (Figures 7 and 8).

Figure 7. AIROD® shaped to accommodate airway anatomy.

Figure 8. ETT advancing down the AIROD®.

Use the proximal tip to lift the epiglottis and expose the vocal cords. Then advance the AIROD® two cm into the trachea followed by the ETT.

Case Presentations

Case 1

54-year-old man with severe coronary artery disease on aspirin and Plavix® with a history of a seizures associated with alcohol withdrawal became unresponsive and a code blue was called. He was found to be apneic with oxygen saturation in the 50s. He was stimulated by the hospitalist and became responsive. He was transferred to the ICU, where he became completely unresponsive again and stopped breathing. He was immediately ventilated with a bag-valve mask, and oxygenation improved to 100%. He then bolted up out of bed and became very combative. Propofol was given and he was laid supine and ventilated with a bag-valve mask. Inspection of his oropharynx revealed a very large tongue, and some missing and multiple sharp teeth with mouth opening of only 2 fingerbreadths. There was blood and emesis in his oropharynx that was suctioned. A Miller 4 blade was inserted into the oropharynx but only a grade 4 view could be obtained. The AIROD® was inserted into the oropharynx in the fully extended and locked position and the proximal tip was used to gently lift the epiglottis, exposing the vocal cords, and improving the view to a grade 2. The AIROD® was advanced 2 cm past the vocal cords and an assistant advanced an 8.0 endotracheal tube down the AIROD® until it was grasped, and the endotracheal tube was advanced successfully past the vocal cords while the assistant held the distal end of the AIROD®. The AIROD® was removed intact without any oropharyngeal or vocal cord trauma.

Case 2

A 63-year-old  5’5 110 kg woman with COPD, morbid obesity, obstructive sleep apnea, atrial fibrillation, diabetes mellitus, and anxiety suffered a cardiac arrest and was successfully resuscitated with placement of a drug eluting stent into the right coronary artery. One week later she required intubation for acute respiratory failure. She was extubated the following day and developed stridor, which resolved with pain medication and racemic epinephrine. Two days later, she developed acute respiratory failure again, with stridor that resolved after receiving 4 mg IV Versed. A diagnosis of paroxysmal vocal cord dysfunction was made. The next day she developed similar symptoms that responded to additional Versed® and Precedex®. The next morning, she became anxious after the Precedex® was stopped and once again developed acute stridor with respiratory failure, responding to Zyprexa® and Versed® momentarily. She was comfortable throughout the day until her stridor resumed, and despite BiPAP she was unable to adequately ventilate. She became obtunded, prompting intubation.

In addition to stridor, her Mallampati was 4, she had a sharp, prominent full set of teeth, an airway opening 1.5 cm, a large tongue with excessive oropharyngeal tissue, false cords, and vocal cord swelling. The AIROD® was preloaded with a 7.0 ETT that had attached to it a 10 mL syringe onto the distal end and tucked it under the patient’s right shoulder with the tip lying flat and pointing laterally, protected with a sterile OR towel. The AIROD® lay at a 45^o to the neck. She was given 20 mg of etomidate and immediately ventilated with a bag-valve mask. A Miller 4 blade was gently inserted into the mouth, revealing a grade 4 view with purulent mucus in her oropharynx. The AIROD® was grasped and used to manipulate the false cords, revealing the true vocal cords while cricoid pressure was applied. A grade 2 view was obtained. The cords were adducted with a posterior glottal chink. The AIROD® was gently passed 2 cm through the tiny opening at the bottom of the vocal cords and used to dilate the area with the smooth bulbous tip. The ETT was then advanced into the trachea while the respiratory therapist held the distal end of the AIROD®. The AIROD® was removed intact without any evidence of oropharyngeal trauma. Successful first-attempt intubation occurred without complications. Bronchoscopy confirmed no tracheobronchial tree trauma.

Case 3

A 71-year-old  5’10’’ tall 101 kg man with non-insulin dependent diabetes mellitus, hypertension, and obesity was intubated 18 days prior for severe ARDS secondary to SARS-CoV-2. He subsequently lost his airway, and the attending physician was unable to intubate using the Glidescope®; so an emergency tracheostomy was performed with placement of a 5.0 Shiley. The evening of the 24^th day of ventilation, he was unable to be ventilated effectively with his PCO2 rising to 73 mmHg with a pH of 7.13. He was on a propofol drip and 10 mg vecuronium was given while he was being ventilated through the 5.0 tracheostomy. He was actively bleeding from his nasopharynx. A Miller 4 blade was gently inserted into his mouth revealing a bloody and swollen oropharynx. A pre-loaded AIROD® was used to gently displace tissue, revealing a grade 1 view. The AIROD® was inserted 1 cm past the vocal cords and the ETT was then advanced slowly into the trachea with no assistant holding the AIROD®. The AIROD® was pulled back as the endotracheal tube was advanced down the trachea, abutting the tracheostomy tube. The ETT balloon was inflated and the AIROD® was removed intact without any evidence of acute oropharyngeal trauma. The single-handed first-attempt intubation was performed in 19 seconds. This was followed by the exchange of the 5.0 tracheostomy for an 8.0 tracheostomy. Bronchoscopy confirmed no acute oropharyngeal or tracheal trauma with the tracheostomy in the correct position in the trachea.

Case 4

A 68-year-old 5’10 126 kg smoker with a past medical history significant for COPD, on home oxygen with multiple intubations in the past was admitted. He had a past medical history of  pulmonary embolism on Eliquis®, deep venous thrombosis with an inferior vena cava filter, obstructive sleep apnea, and obesity. He was diagnosed with COVID-19 pneumonia and treated with BiPAP at 100% FiO₂ for six days in the ICU. He developed ARDS and altered mental status, prompting intubation. Obese, large neck with limited neck mobility, micrognathia, large very dry tongue, sharp teeth with some missing, and a mouth opening 2 cm. He received propofol 200 mg IV and succinylcholine 200 mg IV. A Miller 4 blade gently inserted into oropharynx revealed an anterior glottis with false cords. The AIROD® was used to probe the false cords and advanced gently 5 cm, feeling the tracheal rings to ensure placement in the trachea. An 8.0 ETT was slowly advanced into the trachea using the single-handed first-attempt technique. An endotracheal balloon was inflated and the AIROD® removed intact without any evidence of acute oropharyngeal or tracheal trauma.

Case 5

28-year-old 5’9 man 97 kg with a past medical history significant for alcoholism was admitted. He was currently drinking two liters of vodka daily, had a history of  alcoholic cardiomyopathy and esophageal varices, drank hand sanitizer “to remain drunk”, and developed acute shortness of breath, and felt that his “throat was closing”. He developed very severe stridor with respiratory distress and was transferred to the ICU. Audible stridor could be heard as he arrived. He was in severe respiratory failure, sitting up, and very anxious. He was drooling bloody secretions. He was placed on a 15 L/min 100% FiO₂ non-rebreathing mask. He was obese, had a large large neck with limited mobility, mouth opening 2 cm, protruding large tongue, full set of teeth, micrognathia with severe stridor, and was barely moving any air. He was given 4 mg IV Versed®. A tracheostomy kit was at bedside with a surgeon present. He was given 100 mg IV propofol, then laid flat and quickly placed in the SNIFF position. Bag-valve-mask was performed. SpO2 100%. An additional 100 mg IV propofol was given. A Miller 4 blade barely lifted the tongue when fresh blood was encountered. The blade was advanced gently, and bloody secretions suctioned. A crowded anterior hamburger oropharynx, bleeding with mucosal sloughing and false cords was encountered. The AIROD® pre-loaded with a 6.5 ETT was gently advanced underneath the epiglottis and advanced 3 cm, followed by advancement of the 6.5 ETT. Bag-valve ventilation occurred with poor CO2 detector color change. The ETT was left in place while bag-valve-mask ventilation was performed. SpO2 100%. The AIROD® was pre-loaded with a 7.0 ETT. A second-attempt revealed an air bubble anterior to the ETT. The 6.5 ETT was removed as the AIROD® was advanced towards the air bubble. The AIROD® was used to probe the hamburger glottis and to peel back the false cords revealing a small view of the right vocal cords, followed by advancement of the AIROD® 3 cm. A 7.0 ETT was slowly advanced into the trachea and balloon inflated with no assistant holding the AIROD®. No evidence of acute oropharyngeal trauma. Bronchoscopy revealed no tracheobronchial trauma and confirmed acute adenoviral necrotizing pharyngitis.

Conclusion

Anticipation of a difficult airway should always be considered, and having the necessary tools available can improve first-attempt endotracheal intubation success. Optimizing head positioning can be performed quickly and will help with glottic exposure. Knowing how to use multiple laryngoscopes as well as introducers can make the difference between life and death.

Conflicts of Interest

Evan D. Schmitz, MD is the inventor of the AIROD® and CEO of AIROD Medical, LLC.

Acknowledgments

The author thanks H. Carole Schmitz and Bille J. Maciunas for their editorial comments.

References

1. Sasano N, Morita M, Sugiura T, Sasano H, Tsuda T, Katsuya H. Time progression from the patient's operating room entrance to incision: factors affecting anesthetic setup and surgical preparation times. J Anesth. 2009;23(2):230-4. [CrossRef] [PubMed]
2. Driver B, Prekkar M, Klein L, et al. Effect of use of a bougie vs endotracheal tube and stylet on first-attempt intubation success among patients with difficult airways undergoing emergency intubation a randomized clinical trial. JAMA. 2018;319(21):2179-2189. [CrossRef] [PubMed]
3. Schmitz ED. Decreasing COVID-19 patient risk and improving operator safety with the AIROD during endotracheal intubation. J of Emergency Services. EMSAirway. 11/2020.
4. Adnet F, Borron SW, Dumas JL, Lapostolle F, Cupa M, Lapandry C. Study of the "sniffing position" by magnetic resonance imaging. Anesthesiology. 2001 Jan;94(1):83-6.[CrossRef] [PubMed]
5. Adnet F, Baillard C, Borron SW, et al. Randomized study comparing the "sniffing position" with simple head extension for laryngoscopic view in elective surgery patients. Anesthesiology. 2001 Oct;95(4):836-41. [CrossRef] [PubMed]
6. Schmitz ED, Park K. First-Attempt Endotracheal Intubation Success Rate Using A Telescoping Steel Bougie. Southwest J Pulm Crit Care. 2021;22(1):36-40. doi: [CrossRef]
7. Schmitz ED, Park K. Emergency intubation of a critically ill patient with a difficult airway and avoidance of cricothyrotomy using the AIROD®. J of Emergency Medical Services. 2021;22(1):36-40. 
8. Schmitz ED. Single-use telescopic bougie: case series. Southwest J Pulm Crit Care. 2020;20(2):64-8. [CrossRef]
9. Schmitz ED. AIROD® Case Series: A New Bougie for Endotracheal Intubation. J of Emergency and Trauma Care. 2020;5(2):22.
10. Schmitz ED. The Importance of Head Positioning During Endotracheal Intubation. EMSAirway. Jul 27, 2021. Available at: https://emsairway.com/2021/07/27/the-importance-of-head-positioning-during-endotracheal-intubation/#gref (accessed 4/18/23).
11. Lascarrou JB, Boisrame-Helms J, et al. Video Laryngoscopy vs Direct Laryngoscopy on Successful First-Pass Orotracheal Intubation Among ICU Patients: A Randomized Clinical Trial. JAMA. 2017;317(5):483-493. [CrossRef] [PubMed]
12. Higgs A, McGrath BA, Goddard C, Rangasami J, Suntharalingam G, Gale R, Cook TM; Difficult Airway Society; Intensive Care Society; Faculty of Intensive Care Medicine; Royal College of Anaesthetists. Guidelines for the management of tracheal intubation in critically ill adults. Br J Anaesth. 2018 Feb;120(2):323-352. [CrossRef] [PubMed]
13. Brown CA 3rd, Bair AE, Pallin DJ, Walls RM; NEAR III Investigators. Techniques, success, and adverse events of emergency department adult intubations. Ann Emerg Med. 2015 Apr;65(4):363-370.e1. [CrossRef] [PubMed]

Cite as: Schmitz ED. Essentials of Airway Management: The Best Tools and Positioning for First-Attempt Intubation Success. Southwest J Pulm Crit Care Sleep. 2023;26(4):61-69. doi: https://doi.org/10.13175/swjpccs015-23 PDF

October 2020 Critical Care Case of the Month: Unexplained Encephalopathy Following Elective Plastic Surgery

Natalie Held, MD and Carolyn Welsh, MD

University of Colorado Division of Pulmonary Sciences and Critical Care Medicine

Aurora, CO USA

A 29-year-old woman with no significant medical history presents to the hospital due to progressive encephalopathy, 5 days after undergoing an elective abdominoplasty with abdominal liposuction and breast augmentation. She is somnolent on exam, and is hypoxic to ~60% saturation on room air. She is emergently intubated in the emergency department prior to being admitted to the MICU, and is started on broad-spectrum antibiotics and n-acetyl cysteine (NAC). She has evidence of acute liver failure but her initial work-up for acute liver failure is entirely unrevealing, and her liver function and hemodynamics improve without additional intervention over the initial 3 days of hospitalization. Unfortunately, her mental status does not improve. Despite weaning of all sedation, she shows limited signs of awareness. A lumbar puncture, CT of the head, and electroencephalogram (EEG) are performed and are unremarkable.

What should be done next? (Click on the correct answer to be directed to the second of six pages)

1. Brain magnetic resonance (MRI) imaging
2. Myelography
3. Neurology consultation
4. 1 and 3
5. All of the above

Cite as: Held N, Welsh C. October 2020 Critical Care Case of the Month: Unexplained Encephalopathy Following Elective Plastic Surgery. Southwest J Pulm Crit Care. 2020;21(4):73-9. doi: https://doi.org/10.13175/swjpcc041-20 PDF 

Fluid Resuscitation for Septic Shock – A 50-Year Perspective: From Dogma to Skepticism

Robert A. Raschke, MD

Arooj Kayani, MD 

Samir Sultan, DO

Stephanie Fountain, MD

Moustafa Abidali, DO

Kyle Henry, MD

Banner University Medical Center Phoenix

Phoenix, AZ USA 

Few clinicians would challenge the contention that fluid resuscitation of sepsis improves tissue perfusion thereby protecting end-organs from injury. This is an underlying tenet of current Surviving Sepsis Campaign (SSC) recommendations (1) and Center for Medicare and Medicaid Services (CMS) mandate that hospitals report sepsis bundle compliance as a measure of healthcare quality.  It has persisted for decades despite the lack of convincing empirical evidence that fluid resuscitation improves clinical outcomes. To the contrary, large randomized controlled trials have shown that aggressive intravenous fluid resuscitation prolongs the need for mechanical ventilation (2) and increases mortality in some patients (3) – more on these studies later.  Furthermore, the pathophysiological rationale commonly used to explain why fluid resuscitation ought to be beneficial has been challenged by a growing body of evidence.  This article started as a journal club held by our Pulmonary Critical Care fellows, but we expanded the scope to review other related studies over the past 50 years that challenge the current accepted paradigm of aggressive fluid resuscitation of sepsis and septic shock.

The positive results of River’s early goal-directed therapy (EGDT) trial in the early 2000s (4) were inexplicable to many that followed previous literature. EGDT required aggressive fluid resuscitation to achieve a central venous pressure (CVP) >8-12 cmH₂O, culminating in a mean positive fluid balance >13 L at 72 hours. But it had been recognized for decades that CVP could not reasonably be used in this manner. In 1965, Dr. Max Weil (considered by some the founder of critical care medicine) made the observation that the CVP is primarily an index of right ventricular function rather than an index of volume status (5). The widely-held concept (which has persisted since 1965) that low venous pressure indicates low blood volume was developed using data from normal subjects and was not valid in critical illness. Elevated CVP reflects incompetence of the heart to accept the blood returned to it. As such, CVP ought to be used primarily to limit over-resuscitation rather than to indicate when more fluids are needed (5).

These early observations and decades of corroborating evidence were set-aside for yet another decade as EGDT was systematically endorsed. Near the peak of enthusiasm for EGDT, a meta-analysis of 24 studies demonstrated no significant relationship between CVP and blood volume (r²=0.02) or fluid responsiveness (r²=0.03) (6). A graph from that article based on 1500 simultaneous measurements of CVP and blood volume graphically illustrates the apparent lack of any association, supporting Dr Weil’s clinical observations from over 40 years earlier (Figure 1). 

Figure 1. Graph of simultaneous measurements of blood volume and central venous pressure (CVP) in a heterogenous cohort of 188 ICU patients demonstrating no association between these two variables (r=0.27) (6).

Nevertheless, EGDT was avidly endorsed by authoritarian professional organizations and immense time and effort expended on national and international efforts to promote it’s systematic implementation. Several observational studies showed that systematic implementation of EGDT in healthcare institutions decreased sepsis mortality (7,8). However,  the use of historical controls in these studies allowed other simultaneous changes in ICU practice and the Hawthorne effect to potentially confound their results.

In 2006, the ARDS clinical trials network published a multi-center controlled trial that randomized 1000 patients with acute lung injury to liberal or conservative fluid management (2). Approximately 70% of the patients in the study satisfied current criteria for sepsis (were classified as having sepsis or pneumonia with acute organ system dysfunction). Critical appraisal of the study revealed that >90% of screened patients were excluded, complicated fluid management protocols were unlikely to be practical for routine use and the study was not blinded. But the study methodology was otherwise essentially sound. Liberal fluid management achieved a more positive fluid balance over the first 7 days (+6992 +/-502 mL vs. -136 +/- 491 mL p<0.001), but failed to reduce the incidence of shock or acute renal failure requiring dialysis. It was instead associated with significantly prolonged ventilator dependence (12.1 vs. 14.6 ventilator-free days, p<0.001) and prolonged ICU length-of-stay (11.2 vs. 13.4 ICU-free days, p<0.001).  These results seemed contrary to those of Rivers and we struggled at the time to reconcile the two. Our shared impression at journal club is that aggressive fluid resuscitation followed by permissive hypervolemia, such as seen in the liberal fluid management arm of this study, is still common in current practice. This study suggests that this approach significantly prolongs recovery from acute lung injury. 

Maitland’s study of fluid boluses in African children in 2011 is remarkable as the only large prospective randomized controlled trial (RCT) to study the clinical effect of early fluid resuscitation in patients with severe infections (3). The study randomized children with high fever and clinical evidence of impaired perfusion to three groups: 5% albumin bolus, normal saline bolus or no bolus. The safety monitoring committee ended the study after 3141 of 3600 projected patients had been enrolled, based on evidence that administration of either type of fluid bolus significantly increased mortality (RR 1.45 95%CI: 1.13-1.86 p=0.003). Methodology was limited by available healthcare infrastructure. Although the proportion of patients with sepsis cannot be calculated, 39% had a lactate >5 mmol/L. The study had reasonable internal validity, but significant challenges to external validity – the mean patient age was 23 months, and 57% had malaria.  However, the authors noted: “The excess mortality with fluid resuscitation was consistent across all subgroups, irrespective of physiological derangement (whether or not the patient was in shock) or underlying microbial pathogen, raising fundamental questions about our understanding of the pathophysiology of critical illness.” The authors speculated that the neuro-hormonal vasoconstrictor response to shock might confer protection by reducing perfusion to non-vital tissues and that rapid reversal with fluid resuscitation could therefore be harmful. This specific hypothesis was supported by a post-hoc analysis that showed that the increased mortality associated with fluid boluses could not be explained by an increase in pulmonary or cerebral edema.  Although the generalizability of this study is limited, there is no comparable RCT of fluid boluses in any other group of patients to refute it’s findings.

The review of resuscitation fluids by Myberg and Mythen in 2013 (9) emphasized ongoing uncertainty and reasoned against a protocolized approach driving aggressive fluid resuscitation stating “the requirements for and response to fluid resuscitation vary greatly during the course of any critical illness. No single physiological or biochemical measurement adequately reflects the complexity of fluid depletion or the response to fluid resuscitation.”  They reviewed observational evidence that the development of positive fluid balance and elevated CVP were associated with increased mortality in patients with sepsis. They pointed out that intravenous fluids should be considered as a drug with potentially serious side effects: interstitial edema - and in the case of normal saline, hyperchloremic acidosis and acute kidney injury. They recommended modest amounts of balanced isotonic salt solutions guided by clinical consideration of multiple individual patient factors, cautioned against continuing fluid resuscitation after the first 24 hours of illness and encouraged early initiation of norepinephrine.

Myberg’s review was published about the time that the results of three randomized controlled trials, which cumulatively enrolled 4201 patients at 138 emergency departments and ICUs internationally conclusively refuted any clinical benefit of EGDT (10-12). Shortly thereafter, CMS paradoxically mandated monthly sepsis bundle compliance reporting as a measure of healthcare quality, strongly incentivizing hospitals to systematically institute sepsis bundles, even though they had just been proven to be ineffective.

We greatly enjoyed the review of fluid therapy in sepsis by Marik and Bellomo (13). They argue that the standard pathophysiological explanation for the theoretical benefit of fluid resuscitation in sepsis is contradicted by a growing body of evidence. Septic shock is not characterized by hypovolemia but rather by vasoplegia and injury to the endothelial glycocalyx. Resultant microvascular permeability and propensity to interstitial edema impairs organ function. As such, restoration of vascular tone (including that of capacitance veins) is the preferred initial intervention to restore perfusion. Elevating the CVP > 8 cm H₂O with fluid boluses does not reliably improve preload and cardiac output as commonly supposed. Instead, it most often overfills the heart, inducing acute diastolic dysfunction in a majority of patients. This paradoxically reduces stroke volume and moves the patient onto the flat portion of the Frank Starling curve mitigating any potential augmentation of cardiac fluid by further fluid administration. Elevated CVPs in this setting are not an indication of successful fluid resuscitation but rather a sign of cardiac incompetence to accommodate iatrogenic hypervolemia. Cardiac natriuretic peptides released in response to cardiac overfilling cleave glycoproteins that make up the endothelial glycocalyx further injuring it. Venous back-pressure worsens organ perfusion and increases interstitial edema, particularly affecting the kidneys. However, cellular hypoxia and bioenergetics failure does not occur and is not the cause of lactic acidosis in septic shock as is often supposed. Elevated lactate levels are instead caused by bioenergetic-coupling of epinephrine-induced stimulation of Na/K ATPase activity to aerobic glycolysis. The critical level of oxygen delivery below which oxygen consumption falls is almost never associated with septic shock, and increasing oxygen delivery has been not been shown to improve oxygen consumption or lower lactate levels. Attempts to specifically increase oxygen delivery in sepsis have in fact worsened survival. 

Furthermore, only a minority of patients with sepsis respond with increased stroke volume after a fluid bolus. Hemodynamic improvements seen in “fluid responders” return to baseline within an hour. 95% of administered fluid is rapidly sequestered in tissues where it contributes to organ dysfunction. Goal-directed fluid administration achieves only a transient hemodynamic improvement in a minority of patients at the cost of accumulating injurious tissue edema in all. Analysis of five serial randomized controlled trials that ultimately disproved the efficacy of EGDT shows that sepsis mortality has been fallen significantly over the past 15 years in association with a tendency towards significantly more conservative fluid management (approx. 13L/72hrs vs. 6L/72 hours) suggesting that a more conservative approach to fluid resuscitation may explain improved survival (Figure 2).

Figure 2. Fluid administerered between enrollment and 72 h and 90-day mortality in the control arm of the early goal directed therapy (EGDT) studies performed between 2001 and 2015. APACHE II=APACHE II severity of illness scoring system.

Marik and Bellomo (13) recommend early administration of norepinephrine, which can be safely administered via a well-functioning peripheral intravenous catheter and cautious administration of small volume fluid boluses (200-500 mL) only in patients in whom passive leg raise (a reversible fluid bolus) can be demonstrated to augment stroke volume. They argue that CVP, central venous oxygen saturation and lactate should not be used to guide fluid management, and should in fact not even be measured.

Taken individually, each of these studies seems anomalous in the context of our preconceived notion that aggressive fluid resuscitation must be beneficial. Taken together, they comprise a cohesive argument that ought to change our bedside care.  There certainly isn’t any convincing or enduring empirical evidence that aggressive fluid resuscitation of sepsis is clinically beneficial. There is only flawed pathophysiologic rationale and dogma. The common practice of aggressive fluid resuscitation followed by prolonged permissive hypervolemia should be actively avoided. As we struggle to comply with a CMS mandate regarding sepsis bundle compliance in the face of overwhelming evidence that it doesn’t work, we recommend a focus on early administration of appropriate antibiotics and maintenance of adequate perfusion pressure with vasopressors – the only bundle components likely to be associated with improved patient outcomes.

References

1. Dellinger RP, Levy MM, Rhodes A, et al. ; Surviving Sepsis Campaign Guidelines Committee including The Pediatric Subgroup. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013 Feb;39(2):165-228. [CrossRef] [PubMed]
2. National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, Wiedemann HP, Wheeler AP, Bernard GR, et al. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006 Jun 15;354(24):2564-75. [CrossRef] [PubMed]
3. Maitland K, Kiguli S, Opoka RO, et al. Mortality after fluid bolus in African children with severe infection. N Engl J Med. 2011 Jun 30;364(26):2483-95. [CrossRef] [PubMed]
4. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001 Nov 8;345(19):1368-77. [CrossRef] [PubMed]
5. Weil MH, Shubin H, Rosoff L. Fluid repletion in circulatory shock. JAMA. 1965;192:84–90. [CrossRef] [PubMed]
6. Marik PE, Baram M, Vahid B. Does central venous pressure predict fluid responsiveness? A systematic review of the literature and the tale of seven mares. Chest. 2008 Jul;134(1):172-8. [CrossRef] [PubMed]
7. Ferrer R, Artigas A, Levy MM, et al. Improvement in process of care and outcome after a multicenter severe sepsis educational program in Spain. JAMA. 2008 May 21;299(19):2294-303. [CrossRef] [PubMed]
8. Rhodes A, Phillips G, Beale R, et al. The Surviving Sepsis Campaign bundles and outcome: results from the International Multicentre Prevalence Study on Sepsis (the IMPreSS study). Intensive Care Med. 2015 Sep;41(9):1620-8. [CrossRef] [PubMed]
9. Myburgh JA, Mythen MG. Resuscitation fluids. N Engl J Med. 2013 Sep 26;369(13):1243-51. [CrossRef] [PubMed]
10. ProCESS Investigators, Yealy DM, Kellum JA, Huang DT, et al. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014 May 1;370(18):1683-93. [CrossRef] [PubMed]
11. ARISE Investigators; ANZICS Clinical Trials Group, Peake SL, Delaney A, Bailey M, et al. Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014 Oct 16;371(16):1496-506. [CrossRef] [PubMed]
12. Mouncey PR, Osborn TM, Power GS, et al. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med. 2015 Apr 2;372(14):1301-11. [CrossRef] [PubMed]
13. Marik P, Bellomo R. A rational approach to fluid therapy in sepsis. Br J Anaesth. 2016 Mar;116(3):339-49. [CrossRef] [PubMed] 

Cite as: Raschke RA, Kayani A, Sultan S, Fountain S, Abidali M, Henry K.  Fluid resuscitation for septic shock – a 50-year perspective: from dogma to skepticism. Southwest J Pulm Crit Care. 2016;13(2):65-70. doi: http://dx.doi.org/10.13175/swjpcc073-16 PDF