Non-steroidal antipyretic analgesics (NSAIDs) are widely used in the treatment of critical burns, especially for persistent fever and hyperthermia, and are often needed to relieve symptoms. It is well known that the use of NSAIDs can cause a variety of adverse reactions, which are more common in patients with medical diseases requiring long-term medication such as rheumatoid arthritis and coronary heart disease, and the duration of medication in burn patients is much shorter than that in medical patients, so clinicians are relatively less alert to the adverse reactions of these drugs, or it is difficult to recognize the adverse drug reactions due to the complex manifestations of critical burns. In recent years, several serious adverse reactions related to the application of these drugs were found in the treatment of critical burns in our department, which are reported below.
Clinical data
1, acute kidney injury 1 case
Patient female, 33 years old, was admitted to the hospital for 3 d with multiple flame burns all over the body. Admission diagnosis: burn 95% of the whole body in multiple places, including Ⅲo90%, deep Ⅱo5%, combined with severe inhalation injury. On the day of admission, BUN 2.5 mmol/L, Cr 51 μmol/L, blood potassium 3.3 mmol/L, urinary routine examination was normal; no previous history of renal disease. About 5 weeks after admission, the patient’s BUN, Cr and other renal function indicators showed a gradual increase, while the urine volume did not change significantly, and by 42 d after the injury, the blood Cr had reached 193 μmol/L, which was 378% of the baseline value at the time of admission and 182% of the upper limit of normal value (106 μmol/L). Since no other drugs affecting renal function were used at that time or in the past, the renal injury was considered to be the result of adverse drug reactions to NSAIDs. The patient recovered after 6 dialysis sessions and renal function gradually returned to normal. The patient had no pre-renal or post-renal factors such as shock or ureteral stones before the onset of the disease, and no history of nephrotoxic drugs such as aminoglycosides, but since 1 week after the injury, the patient had fever almost every day, so high doses of lysergic acid, indomethacin, and acetaminophen were used as antipyretics, alternating with as few as one or as many as three per day, which was the main cause of renal injury. The renal function changes and the use of NSAIDs in the patient 1 week before the onset of the disease are shown in Table 1.
Table 1 Changes in some of the patients’ renal function indices and the use of NSAIDs
Days after injury
BUN
(mmol/L)
Cr
(μmol/L)
K+
(mmol/L)
Urine volume
(ml)
NSAID dosage
36d
6.3
38
3.9
3255
Lysergic acid 0.75g
Indomethacin 0.1g
Acetaminophen 0.8g
38d
11.6
85
4.3
1730
Indomethacin 0.1g
Acetaminophen 1.6g
40d
21.0
149
4.8
2620
Lysergic acid 1.0g
Indomethacin 0.1g
42d
22.0
193
6.1
3420
None
2. 1 case of acute thrombocytopenia
The patient was male, 39 years old, admitted to the hospital for flame burns 2hr. Admission diagnosis: burns 94% whole body multiple, including Ⅲo 90%, deep Ⅱo 4%, combined with moderate to severe inhalation injury. Blood count on the day of admission showed: PLT 232×1012/L; no previous history of hematologic disease. The patient’s PLT count decreased significantly from 32 d after injury to the lowest point of 74×1012/L at 35 d after injury, during which time there was no significant deterioration and no other drugs affecting PLT were applied. /L at 36 d, 92×1012/L at 37 d, and 135×1012/L at 38 d, returning to normal levels. As in example 1, the alleviation of persistent hyperthermia was the main reason for the previous high application of NSAIDs. As an example, going back to 15 d before the onset of the disease, a total of 14 d of NSAIDs were applied, with a total of 3.75 g of lysergic acid (5 times), 1.5 g of indomethacin (15 times), and 6.4 g of acetaminophen (8 times). See Table 2.
Table 2 Changes in PLT, some liver function indicators and NSAID use in patients
Days after injury
PLT
(×1012/L)
ALT
(U/L)
TBil
(μmol/L)
DBil
(μmol/L)
NSAID dosage
32d
230
294
41
10
Lysergic acid 0.75g
33d
167
147
23
9
Lysergic acid 0.75g
Indomethacin 0.1g
34d
100
122
39
13
Lysergic acid 0.75g
35d
74
110
72
8
None
38d
135
201
78
36
None
40d
132
126
39
22
None
3. 1 case of acute liver function injury
The patient was the same as the previous case, with no previous history of liver disease or alcohol abuse. On the day of admission, ALT 36 U/L, TBil 40μmol/L (due to acute hemolysis caused by heat), DBil 5.0μmol/L, negative for hepatitis B 2.5 and hepatitis C virus antibody. About 1 week after admission, the patient’s liver function indexes such as ALT, TBil and DBil were gradually increased and fluctuated repeatedly, and he was treated with hepatoprotective drugs (glucuronolactone, polyenylphosphatidylcholine and reduced glutathione), which did not improve or deteriorate significantly until about 1 month after injury. By 35d after the injury, the liver function indexes still maintained certain fluctuation after stopping NSAIDs, but the overall trend was decreasing, and by 60d after the injury (25d after stopping the drug), the liver function basically recovered, and the indexes were: ALT 47 U/L, TBil 22μmol/L, DBil 5.0μmol/L, basically close to normal. During the interval (40 d after injury), the patient developed deep venous catheter infection, which caused rapid deterioration of liver function, with TBil reaching a maximum of 342 μmol/L, DBil reaching 90.3 μmol/L, and ALT 187 U/L, prolonging the recovery time of liver function. See Table 2.
4. 4 cases of upper gastrointestinal hemorrhage
4 cases, all male, 2 cases in children and 2 cases in adults; age 5 to 35 years, mean age 19.3±16.5 years; burn area 25% to 95%, mean 58.8%±36.4%; Ⅲ degree area 15% to 95%, mean 48.7%±35.4%. The first occurrence of gastrointestinal bleeding (positive latent blood test in stool or gastric juice) was from 3 to 6 d after injury, and major bleeding occurred from 11 to 47 d after injury, with an average of 21.5 ± 17.2 d. All were painless bleeding, and all showed shock, and the lowest Hb value at the time of major bleeding was 34 to 67 g/L, with an average of 48.3 ± 13.7 g/L; transfusion volume was 16 to 52 U, with an average of The three cases underwent gastroscopy and all ulcers were located in the duodenum at the junction of the bulb, postbulb, descending and horizontal parts; all were small arterial pulsatile bleeding; one case was multiple (2) and two cases were single; ulcer size was 0.5×0.5cm～2×2cm; no or little moss on the surface of the ulcer, blood clot or active bleeding, clear border, and red and swollen surrounding tissues were visible. All four cases in this group had no history of ulcers before the injury, while all had a history of continuous and heavy use of NSAIDs drugs after the injury due to persistent hyperthermia. See Table 3.
Table 3 Clinical conditions of the 4 cases of upper gastrointestinal hemorrhage
Case
Age
(years)
Burn area
(% body surface area)
Bleeding time
(days after injury)
Hb minimum (g/L)
Blood transfusion volume
(U)
Ulcer site
Size of ulcer (cm)
Treatment method
Ending
First
Hemorrhage
Case 1
5
30
4
11
47
20
Ball part
1×1.5
Surgery
Survival
Case 2
5
25
5
11
34
16
-
-
Conservative
Survival
Example 3
32
95
3
47
45
52
Behind the ball
1.5×1.5
Conservative
Death
Example 4
35
85
6
19
67
48
Junction of descending part and horizontal part
0.5×0.5
Surgery
Survival
Discussion
Burns, especially large critical burns, are often followed by a shock phase with hyperthermia, which can last for a long time, in some patients until the trauma is largely closed. Such a prolonged fever can be difficult to manage. Physical cooling can achieve the goal but is short-lived, making the application of NSAIDs the easiest choice for clinicians. The dosage of drugs used to reduce fever is often large, and therefore, although the duration of administration may not be long, it is sufficient to cause serious adverse effects in some patients. Patients with critical burns can also often develop a variety of visceral complications during the natural course of the disease, such as stress ulcers (Curling ulcers) and liver and kidney damage, making it difficult to identify adverse reactions to this class of drugs in a mixed bag. Therefore, clinical reports and analyses of such problems are also rare.
1. Gastrointestinal mucosal injury
Gastrointestinal mucosal damage is the most clinically familiar adverse reactions to NSAIDs. The mechanism of injury includes local and systemic damage of the drug, local damage refers to the direct stimulation of the mucosa by the drug, and the systemic effect is that NSAIDs inhibit the conversion of arachidonic acid into prostaglandins (PG) by inhibiting cyclooxygenase (COX). The latter is the main factor causing ulcers.
In the author’s opinion, NSAIDs were an important cause in the process of developing life-threatening hemorrhage from the initial small amount of gastrointestinal bleeding in the four cases in this group. Other major factors contributing to the development of this disorder were inadequate early shock resuscitation, surgery and prolonged duration of anesthesia, etc. NSAIDs together with these factors contributed to the development of hemorrhage. According to the literature, the use of NSAIDs can lead to damage to the gastric mucosa in a few hours to a few days, and acute ulcers can occur in more than 1 week, and ulcer bleeding induced by NSAIDs can account for 16.5% of upper gastrointestinal bleeding; the presence of serious systemic diseases and gastrointestinal mucosal damage are high-risk factors for serious gastrointestinal reactions to the application of NSAIDs. The four cases in this group are all large deep burns, and a small amount of bleeding occurred in the early post-injury period, which means that there are high-risk factors for serious gastrointestinal reactions caused by NSAIDs, and the application of such drugs under such conditions is likely to be a key factor leading to the aggravation of the original lesion and eventually to the occurrence of hemorrhage.
2.Acute kidney injury
Drug-induced acute kidney injury, the most clinically known is the aminoglycoside antibiotics, the other drugs caused by kidney injury is often due to lack of awareness and lack of vigilance. It has been reported that NSAIDs cause pharmacogenic acute renal failure can account for 7% of all patients with acute renal failure, accounting for 36% of pharmacogenic acute renal failure, and most often seen in women, especially non-oliguric renal failure is most common. The present case is a typical case of non-oliguric acute kidney injury caused by NSAIDs. According to the definition of acute kidney injury developed by the Acute Kidney Injury Expert Consensus Group in 2005, an absolute increase in serum creatinine level of more than 25 μmol/L or more than 50% in 48 h. This patient met the diagnostic criteria. The main cause of renal injury from this class of drugs remains the inhibition of PG synthesis by NSAIDs. The kidney is an important site of PG synthesis and an important target organ for PG action. Under normal conditions, PG plays a minor role in the kidney, but when renal perfusion is reduced, PG can play an important compensatory role, mainly including: maintaining intrarenal environmental stability and water-electrolyte balance; controlling renin release; and dilating renal blood vessels to increase renal blood flow and glomerular filtration rate when needed. In normal populations, the renal changes induced by PG inhibition by NSAIDs can be compensated, but the susceptibility to renal damage is greatly increased under conditions of a number of causative factors, including reduced renal perfusion due to various causes of effective blood volume deficit (including hyperthermia) and the combined application of similar drugs. Inadequate effective blood volume can further activate the renin-angiotensin system and exacerbate ischemic renal injury.
Since most renal injuries caused by NSAIDs are of the non-oliguric type, monitoring of this condition should not be simply a matter of observing changes in urine output. Given the difficulties in measuring weight changes in critically burned patients, it is recommended that regular blood creatinine checks are appropriate. In terms of treatment, most of the acute kidney damage caused by antipyretic and analgesic drugs has a good prognosis and can generally be recovered after stopping the drugs, the key lies in early diagnosis, symptomatic treatment and active protection of kidney function.
3.Acute liver injury
The liver injury caused by NSAIDs is a kind of drug-related liver injury. The diagnostic criteria are: ① the regularity of time between drug treatment and the appearance of symptoms: the latency period of liver injury after the initial use of drugs is within 5~90d (prompt), the latency period of those with idiosyncratic reactions can be less than 5d, and the latency period of liver injury caused by slow metabolizing drugs can be >90d (suspicious). The latency period of hepatocellular injury after drug discontinuation is ≤15d, and the latency period of cholestatic liver injury is ≤30d (suspicious). ② rapid improvement of liver biochemical indexes after discontinuation of the drug: serum ALT decreases >50% (highly suggestive) within 8d or ≥50% (suggestive) within 30d for hepatocellular injury type; serum ALP or TB decreases ≥50% (suggestive) within 180d for cholestatic type. ③Liver injury due to other etiologies or diseases must be excluded. ④ Positive reaction to re-medication. ① + ② + ③ of the above diagnostic criteria, or 2 of the first 3 items + ④, can be diagnosed as drug-related liver injury. According to this criterion, the cases presented in this paper can be suggested as liver injury caused by NSAIDs; however, based on the complexity of critical burn conditions, some other causative factors such as toxin absorption are also important causative factors of liver injury. In terms of mechanism of injury, except for a few NSAIDs such as aspirin, which have intrinsic hepatotoxicity, most of the damage to the liver from these drugs is an idiosyncratic somatic response, i.e., individual hypersensitivity or abnormal metabolism to the drug. The former has a higher incidence and a shorter latency period but is related to the dose of the drug used, while the latter is the opposite and often unpredictable in occurrence. In terms of clinical manifestations, most of the acute liver damage caused by NSAIDs is dominated by malaise, decreased appetite, depression, nausea and jaundice, and the changes in blood biochemistry are more prominent in the form of elevated transaminases, which lack specificity and can be almost completely hidden in the complex clinical phenomena of critical burns and are unrecognizable, therefore, it is necessary to strengthen the vigilance of adverse reactions to this class of drugs and to detect them from the hints of clinical manifestations The clue.
4. Thrombocytopenia
Thrombocytopenia in patients with critical burns is mostly seen in sepsis, which is one of the signs of a dangerous condition. In this case, when the platelet count decreased rapidly, there was no change in the condition, and the infection factor could be excluded. The risk of indomethacin is greater. The mechanism of hematologic adverse reactions caused by this class of drugs has not been elucidated, and may be caused by metabolic reactions. According to a retrospective analysis of 196 articles and 307 cases of drug-induced thrombocytopenia published from 1996 to 2006 in China, it can be found that thrombocytopenia caused by antipyretic and analgesic drugs accounted for 4.89% of all cases and ranked the 7th.
In conclusion, due to the complexity and diversity of critical burn conditions, adverse reactions caused by NSAIDs are often mixed with them, so in clinical practice, we should be vigilant and identify them, especially the less common adverse reactions other than GI adverse reactions, and seek strategies to reduce their damage, such as adding misoprostol to prevent gastrointestinal mucosal damage, or using more effective physical cooling measures to reduce or avoid the use of this The use of such drugs should be reduced or avoided.